However, the precise dose reduction in this patient population is not known, and subsequent dose modifications should be considered based on individual patient tolerance to treatment see Tables 1—4. In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT3 blocker e. Physicians should also consider providing patients with an antiemetic regimen e. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. Other drugs should not be added to the infusion solution.
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The 8. Postmarketing Experience The following adverse reactions have been identified during post approval use of Irinotecan hydrochloride injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Myocardial ischemic events have been observed following Irinotecan hydrochloride injection therapy. Thromboembolic events have been observed in patients receiving Irinotecan hydrochloride injection. Symptomatic pancreatitis, asymptomatic pancreatic enzyme elevation have been reported. Increases in serum levels of transaminases i. Hyponatremia, mostly with diarrhea and vomiting, has been reported.
Transient dysarthria has been reported in patients treated with Irinotecan hydrochloride injection ; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of Irinotecan. Interaction between Irinotecan and neuromuscular blocking agents cannot be ruled out. Irinotecan has anticholinesterase activity, which may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized.
Infections: fungal and viral infections have been reported. The appropriate starting dose for patients taking these or other strong inducers such as rifampin and rifabutin has not been defined. Consider substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of Irinotecan hydrochloride injection therapy.
Do not administer strong CYP3A4 inducers with Irinotecan hydrochloride injection unless there are no therapeutic alternatives. Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting Irinotecan hydrochloride injection therapy. Available postmarketing and published data reporting the use of Irinotecan hydrochloride injection in pregnant women, are insufficient and confounded by the concomitant use of other cytotoxic drugs, to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Advise pregnant women of the potential risk to a fetus. In the U. Data Animal Data Radioactivity related to 14C-Irinotecan crosses the placenta of rats following intravenous administration.
Lactation Risk Summary Irinotecan and its metabolites are present in human milk. There is no information regarding the effects of Irinotecan on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from Irinotecan hydrochloride injection in the breastfed child, advise lactating women not to breastfeed during treatment with Irinotecan hydrochloride injection and for 7 days after the final dose. Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status in female patients of reproductive potential prior to initiating Irinotecan hydrochloride injection.
Contraception Irinotecan hydrochloride injection can cause fetal harm when administered to a pregnant woman. Males Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use condoms during treatment and for 3 months after the final dose of Irinotecan hydrochloride injection [see Nonclinical Toxicology Infertility Females Based on postmarketing reports, female fertility may be impaired by treatment with Irinotecan hydrochloride injection.
Menstrual dysfunction has been reported following Irinotecan hydrochloride injection administration. Males Based on findings from animal studies, male fertility may be impaired by treatment with Irinotecan hydrochloride injection [see Nonclinical Toxicology Pediatric Use The effectiveness of Irinotecan in pediatric patients has not been established.
Results from two open-label, single arm studies were evaluated. Grade neutropenia was experienced by 54 Neutropenia was complicated by fever in 15 8. Grade diarrhea was observed in 35 This adverse event profile was comparable to that observed in adults. This single agent therapy was followed by multimodal therapy.
Accrual to the single agent Irinotecan phase was halted due to the high rate The adverse event profile was different in this study from that observed in adults; the most significant grade 3 or 4 adverse events were dehydration experienced by 6 patients Minimal accumulation of Irinotecan and SN was observed in children on daily dosing regimens [daily x 5 every 3 weeks or daily x 5 x 2 weeks every 3 weeks].
Renal Impairment The influence of renal impairment on the pharmacokinetics of Irinotecan has not been evaluated. Therefore, use caution in patients with impaired renal function. Irinotecan hydrochloride injection is not recommended for use in patients on dialysis. Hepatic Impairment Irinotecan clearance is diminished in patients with hepatic impairment while exposure to the active metabolite SN is increased relative to that in patients with normal hepatic function.
The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in total bilirubin and transaminase concentrations.
Therefore, use caution when administering Irinotecan hydrochloride injection to patients with hepatic impairment. Overdosage In U. The adverse events in these patients were similar to those reported with the recommended dosage and regimen.
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 Irinotecan hydrochloride injection. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications. Irinotecan Description Irinotecan hydrochloride injection, USP is an antineoplastic agent of the topoisomerase I inhibitor class.
Irinotecan hydrochloride injection, USP is supplied as a sterile, pale yellow, clear, aqueous solution. Each milliliter of solution contains 20 mg of Irinotecan hydrochloride on the basis of the trihydrate salt , 45 mg of sorbitol, NF, and 0. The pH of the solution has been adjusted to 3. Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata or is chemically synthesized.
It is slightly soluble in water and organic solvents. Its structural formula is as follows: Irinotecan - Clinical Pharmacology Mechanism of Action Irinotecan 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 and its active metabolite SN bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks. Mammalian cells cannot efficiently repair these double-strand breaks. Pharmacodynamics Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN SN is formed from Irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain.
SN is approximately times as potent as Irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. The precise contribution of SN to the activity of Irinotecan is thus unknown. Both Irinotecan and SN exist in an active lactone form and an inactive hydroxy acid anion form.
A pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favors the hydroxy acid anion form. Administration of Irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.
Pharmacokinetics After intravenous infusion of Irinotecan in humans, Irinotecan plasma concentrations decline in a multiexponential 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 is about 10 to 20 hours. The half-lives of the lactone active forms of Irinotecan and SN are similar to those of total Irinotecan and SN, as the lactone and hydroxy acid forms are in equilibrium.
Maximum concentrations of the active metabolite SN are generally seen within 1 hour following the end of a minute infusion of Irinotecan.
CAMPTOSAR PACKAGE INSERT PDF
Shaktitaur Table 8 lists the grade 3 and 4 adverse events reported in the patients enrolled to all treatment arms of the two studies described in Clinical Studies Studies 3, 4, and 5 Data from three open-label, single-agent, clinical studies, involving a total of patients in 59 centers, support the use of CAMPTOSAR in the treatment of patients with metastatic cancer of the colon or rectum that has recurred or progressed following treatment with 5-FU-based therapy. Irinotecan is a camptozar of camptothecin. Table 8 describes the recommended dose modifications during a course of therapy with the weekly dosage schedule and at the start of each subsequent course of therapy with both the weekly or everyweek dosage schedules. Several published guidelines for handling and disposal of anticancer agents are available. National Study Commission on Cytotoxic Exposure. 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. New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation.
HIGHLIGHTS OF PRESCRIBING INFORMATION
Mezikasa Once-EveryWeek Dosage Schedule A total of patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: Studies Evaluating the Weekly Dosage Schedule Data from three open-label, single-agent, clinical studies, involving a total of patients in 59 centers, support the use of CAMPTOSAR in the insertt of patients with metastatic cancer of the colon or rectum that has recurred or progressed following treatment with fluorouracil 5-FU -based therapy. Data from three open-label, single-agent, clinical studies, involving a total of patients in 59 centers, support the use of CAMPTOSAR in the treatment of patients with metastatic cancer of the colon or rectum camptosxr has recurred or progressed following treatment with fluorouracil 5-FU -based therapy. Camptosar Full Prescribing Studies 3, 4, and 5 Data from three open-label, single-agent, clinical studies, involving a total of patients in 59 centers, support the use of CAMPTOSAR in the treatment of patients with metastatic cancer of the colon or rectum that has recurred or progressed following treatment with 5-FU-based therapy. In Study 2, the multivariate analysis on all 15 subscales did not indicate a statistically significant difference between irinotecan and infusional 5-FU.
However, the precise dose reduction in this patient population is not known, and subsequent dose modifications should be considered based on individual patient tolerance to treatment see Tables 1 — 4. Premedication It is recommended that patients receive premedication with antiemetic agents. In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT3 blocker e. Physicians should also consider providing patients with an antiemetic regimen e. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. Preparation of Infusion Solution Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe.