Irinotecan

 

Irinotecan

Irinotecan 20mg/ml Injection



Irinotecan
20mg/ml Injection

Each mL of Irinotecan Hydrochloride Injection, USP contains 20 mg irinotecan (on the basis of the trihydrate salt); 45 mg sorbitol; 0.9 mg of lactic acid, USP and Water for Injection, USP. When necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid.

Irinotecan Hydrochloride Injection, USP is available in single-dose amber glass vials in the following package size:

			*   40 mg/2 mL (20 mg/mL)
			* 100 mg/5 mL (20 mg/mL)
			* 500 mg/25 mL (20 mg/mL)

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

Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from light. Keep the vial in the carton until the time of use.

Inspect the vial for damage and visible signs of leaks before removing from the carton. If damaged, incinerate the unopened package.

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 0.9 mg of lactic acid, USP and Water for Injection, USP. The pH of the solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan Hydrochloride Injection, USP is intended for dilution with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion. The preferred diluent is 5% Dextrose Injection, USP.


Irinotecan
20mg/ml Injection

What is in this leaflet

Please read this leaflet carefully before being treated with IRINOTECAN.

This leaflet answers some common questions about IRINOTECAN.
It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking IRINOTECAN against the benefits they expect it will have for you.

Ask your doctor or pharmacist, if you have any concerns about being treated with this medicine.

Keep this leaflet.

You may need to read it again.

What IRINOTECAN is used for

IRINOTECAN contains the active ingredient, irinotecan  hydrochloride.

It is used to treat bowel cancer which has spread to other parts of the body. Cancer, which has spread, cannot be treated by surgery alone and one of the options in this situation is treatment with an anticancer medicine, known as chemotherapy.

IRINOTECAN may be used once spread of cancer beyond the bowel is first diagnosed. At this time IRINOTECAN will be given in combination with other anticancer medicines. Alternatively, IRINOTECAN is used alone when the cancer has not responded or has returned after initial treatment.

Your doctor may have prescribed IRINOTECAN for another reason.

Ask your doctor if you have any questions about why IRINOTECAN has been prescribed for you.

Use in children
It is not known if IRINOTECAN is safe and effective in the treatment of children.

Before being treated with IRINOTECAN

Some information is provided below. However, always talk to your doctor if you have concerns or questions about your treatment.

When IRINOTECAN must not be given

IRINOTECAN must not be given if you:

  • are allergic to irinotecan hydrochloride, or any of the other ingredients listed at the end of this leaflet.
  • are or may become pregnant
  • are breastfeeding or intend to breast-feed.

Before treatment with IRINOTECAN
You should only be treated with IRINOTECAN by a doctor who is experienced in treating patients with cancer. Treatment will normally take place in a hospital because of the need for hospital facilities and skilled personnel.

You will probably feel nauseous and have diarrhoea, vomiting, stomach cramping and possibly infections during or after treatment with IRINOTECAN .

It is likely that your doctor will give you one or more medicines before administering IRINOTECAN , which will help stop you vomiting or feeling sick after the treatment. You will probably also have a blood test before each treatment.

You should tell your doctor if:

  • you are 65 years of age or older
  • you have or have had liver disease; kidney disease or heart disease
  • you have previously been treated with radiation therapy
  • you have diabetes or asthma
  • you have constipation or difficulty urinating
  • you have hereditary fructose intolerance
  • you have Crigler-Najjar syndrome or Gilbert's syndrome
  • you are going to be vaccinated (have an injection to prevent a certain disease)

If you have not told your doctor about any of the above, tell him/ her before you are given IRINOTECAN .

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and IRINOTECAN may interfere with each other. In particular, tell your doctor if you are taking:

  • laxatives (eg. for constipation)
  • diuretics (medicines which make you pass urine more frequently eg. for heart disease)
  • any medicine for nausea or diarrhoea
  • dexamethasone (may be used to treat eg. skin diseases, asthma or other allergic disorders)
  • anti-convulsants used to treat seizures
  • St. Johns Wort, a herbal medicine used to treat depression
  • Ketoconazole, used to treat fungal infections.

These medicines may be affected by IRINOTECAN or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Your doctor can tell you what to do if you are taking any of these medicines.

Treatment with IRINOTECAN

How IRINOTECAN is given
IRINOTECAN will be given to you by your doctor. It is diluted and given by slow infusion into a vein over a period of 90 minutes.

It is recommended that IRINOTECAN be given in different treatment courses depending on whether IRINOTECAN is given alone or in combination with other anticancer medicines.

When IRINOTECAN is given in combination, treatment courses are of 6 weeks' duration given either weekly or fortnightly. Rest periods of 1 or 2 weeks are incorporated into the 6-week courses.

When IRINOTECAN is given alone, treatment courses include IRINOTECAN being given weekly for 4 weeks followed by a 2-week rest period and IRINOTECAN being given once every 3 weeks.

Depending on your response, treatment courses may be repeated more than once.

It is recommended that treatment with IRINOTECAN should be interrupted if you get severe diarrhoea or other intolerable side effects.

Dose
The recommended dose for IRINOTECAN varies between 125mg/m2 and 350mg/m2 (based on body surface area), depending on the dosing schedule.

Your doctor will decide the dose of IRINOTECAN to be given.

Ask your doctor if you want more information on the dose of IRINOTECAN and the other medicines that you will be receiving and how they are given.

After your first treatment course, the dose of IRINOTECAN may be increased by your doctor if you have not had too many side effects.

Your doctor will lower the dose or stop treatment if you have serious side effects, particularly diarrhoea or changes appearing in your blood tests.

In case of overdose
Overdose is unlikely as treatment will be given in hospital under the supervision of a doctor. The possible effects of overdose are the same as those listed below under Side Effects.

Tell your doctor immediately if you do not feel well while being given IRINOTECAN .

While being treated with IRINOTECAN

Things you must do
Keep all appointments with your doctor and always discuss with your doctor any problems during or after treatment with IRINOTECAN .

Tell your doctor as soon as possible if diarrhoea occurs.

Diarrhoea is a common side effect of IRINOTECAN . If untreated, severe diarrhoea can be life-threatening.

Your doctor will prescribe loperamide (an antidiarrhoeal) for you to take in case you get diarrhoea after treatment. You should start taking loperamide, when you first have poorly formed or loose stools or bowel movements more frequent than you would normally expect.

You must tell your doctor if you cannot get diarrhoea under control within 24 hours after taking loperamide.

You should not take loperamide for more than 48 hours.
Also tell you doctor if you develop a fever in addition to the diarrhoea.

In these cases, your doctor may give you antibiotics. If the diarrhoea or fever persists you may become dehydrated and need to go to hospital for treatment.

You may need to take antibiotics if there are changes in your blood tests indicating a lack of white blood cells. Symptoms of this may include frequent infections such as fever, severe chills, and sore throat or mouth ulcers. If this persists, you may need to go to hospital for treatment.

If you have severe stomach cramps you may need to be treated with antibiotics.

You must use a reliable method of contraception (birth control) while being treated with IRINOTECAN .
However, if pregnancy occurs, consult your doctor.

Things you must not do
Because of the risk of diarrhoea, do not take laxatives during treatment courses with IRINOTECAN . Talk to your doctor if you need more information about this.

Do not start taking any other medicines, prescription or not, without first telling your doctor or pharmacist.

Side effects

Like all other medicines, IRINOTECAN may cause unwanted side effects. Side effects are very common with anti-cancer medicines such as

IRINOTECAN and they may be severe. Deaths have occurred which, in some cases, may have been related to treatment.

Tell your doctor immediately if you get any of the following side effects:

  • diarrhoea
  • start to vomit
  • develop a fever or any type of infection
  • fainting, light-headedness or dizziness
  • bloody or black stools
  • cannot eat or drink due to nausea or vomiting.

The above side effects may be serious. You may need urgent medical attention.

Very common side effects (occurring in over 50% of patients) are:

  • diarrhoea or stomach cramps; may occur early (during or shortly after a treatment) or late (usually more than 24 hours after treatment)
  • nausea, vomiting, loss of appetite
  • anaemia which may make you weak and light-headed or may cause you to faint
  • increased risk of infections including severe infections
  • weakness
  • hair loss

Common side effects (occurring in 10-50% of patients) are:

  • constipation, flatulence (passing wind), sore mouth, heartburn
  • fever (increased body temperature), chills, headache, back pain or other types of pain, infection, fluid retention which results in swelling
  • weight loss, dehydration
  • runny nose or eyes, increased saliva, sweating or flushing
  • skin rash
  • coughing, difficulty breathing
  • difficulty sleeping or dizziness.

Less common side effects (occurring in less than 10% of patients) are:

  • increased risk of bleeding
  • severe fever associated with a reduction in white blood cell numbers
  • bleeding from the bowel
  • jaundice (yellowing of skin and eyes)
  • severe breathing difficulties
  • generally feeling unwell
  • abnormal manner of walking
  • fungal infections (e.g. thrush)
  • kidney problems
  • problem speaking

In addition to the above side effects the following have also been reported:

allergic reactions; some of the symptoms of an allergic reaction may include: rash, itching or hives on the skin. In more severe cases symptoms may also include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body

  • pins and needles
  • abdominal bloating and/or pain
  • chest pains
  • hiccups.

Other side effects not listed above may happen in some people. Some of these side effects can only be found when your doctor does tests to check your progress.

Rare side effects of IRINOTECAN have also been reported. These include effects on the heart and blood vessels such as:

  • slowed heart beat
  • fainting
  • blackouts
  • blood clots
  • swelling and redness along a vein, which is extremely tender when touched
  • chest pains
  • heart attack
  • stroke.

Your doctor has information on monitoring for such side effects and their treatment. A very small number of patients have died suddenly while on irinotecan hydrochloride.

Tell your doctor as soon as possible if you experience any side effects, including any effects not listed above.

After treatment with IRINOTECAN

Storage
IRINOTECAN will normally be stored in a hospital.
It should be stored below 25°C and should be protected from light (kept in the packaging before use).

IRINOTECAN must never be frozen.

Product description

What it looks like
IRINOTECAN is a sterile, pale yellow, clear fluid for injection supplied as 2, 5 or 50 millilitres (mL) in amber glass vials. Each vial is for single use only and is packaged singly in a foil/plastic blister contained within an outer carton to protect against inadvertent breakage and leakage. It is recommended that the unopened blister should remain in the carton until time of use.

Ingredients
The active ingredient in IRINOTECAN is irinotecan hydrochloride. There are 20 milligrams of irinotecan hydrochloride in 1 mL of IRINOTECAN.

Other ingredients are sorbitol, lactic acid, sodium hydroxide and water injections.


Irinotecan
20mg/ml Injection

INDICATIONS AND USAGE
  • Irinotecan Hydrochloride Injection, USP is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
DOSAGE AND ADMINISTRATION

Colorectal Single Agent Regimens 1 and 2
Administer Irinotecan Hydrochloride Injection, USP as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 1.

A reduction in the starting dose by one dose level of Irinotecan Hydrochloride Injection, USP may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.

Table 1. Single-Agent Regimens of Irinotecan Hydrochloride Injection, USP and Dose Modifications
Regimen 1 (weekly)a 125 mg/m2 intravenous infusion over 90 minutes, days 1, 8, 15, 22 then 2-week rest
Starting Dose and Modified Dose Levelsc(mg/m2)
Starting Dose Dose Level -1 Dose Level -2
125 100 75
Regimen 2 (every 3 weeks)b 350 mg/m2 intravenous infusion over 90 minutes, once every 3 weeksc
Starting Dose and Modified Dose Levels (mg/m2)
Starting DoseDose Level -1Dose Level -2
350300250
a       Subsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements depending upon individual patient tolerance.

b       Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance.

c       Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.

Dose Modifications
Based on recommended dose-levels described in Table 1, Single-Agent Regimens of Irinotecan Hydrochloride Injection, USP and Dose Modifications, subsequent doses should be adjusted as suggested in Table 2, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity.

Table 2. Recommended Dose Modifications for Single-Agent Schedulesa 
A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm3, and the platelet count has recovered to ≥100,000/mm3, 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 Irinotecan Hydrochloride Injection, USP.
Worst Toxicity
NCI Gradeb (Value)
During a Cycle of Therapy At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cyclea

WeeklyWeeklyOnce 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 levelMaintain dose levelMaintain dose level
2 (1000 to 1499/mm3)↓ 25 mg/m2 Maintain dose level Maintain dose level
3 (500 to 999/mm3)Omit dose until resolved to
≤ grade 2, then ↓ 25 mg/m2 
↓ 25 mg/m2  ↓ 50 mg/m2  
4 (<500/mm3)Omit dose until resolved to
≤ grade 2, then ↓ 50 mg/m2
↓ 50 mg/m2↓ 50 mg/m2 
Neutropenic feverOmit dose until resolved, 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 levelMaintain dose levelMaintain dose level
2 (4-6 stools/day > pretx)↓ 25 mg/m2 Maintain dose levelMaintain dose level
3 (7-9 stools/day > pretx) Omit dose until resolved to
≤ grade 2, then ↓ 25 mg/m2 
↓ 25 mg/m2↓ 50 mg/m2 
4 (≥10 stools/day > pretx)Omit dose until resolved to
≤ grade 2, then ↓ 50 mg/m2
↓ 50 mg/m2↓ 50 mg/m2
Other nonhematologicd toxicities
1Maintain dose level Maintain dose level Maintain dose level
2↓ 25 mg/m2 ↓ 25 mg/m2 ↓ 50 mg/m2 
3Omit dose until resolved to
≤ grade 2, then ↓ 25 mg/m2 
↓ 25 mg/m2  ↓ 50 mg/m2  
4 Omit dose until resolved to
≤ grade 2, then ↓ 50 mg/m2 
↓ 50 mg/m2 ↓ 50 mg/m2 
a       All dose modifications should be based on the worst preceding toxicity

b       National Cancer Institute Common Toxicity Criteria (version 1.0)

c       Pretreatment

d       Excludes alopecia, anorexia, asthenia

Dosage in Patients with Reduced UGT1A1 Activity
When administered as a single-agent, a reduction in the starting dose by at least one level of Irinotecan Hydrochloride Injection, USP should be considered for patients known to be homozygous for the UGT1A1*28 allele. 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 1-2).

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.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of Irinotecan Hydrochloride Injection, USP. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed.

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.

Irinotecan Hydrochloride Injection, USP 20 mg/mL is intended for single use only and any unused portion should be discarded.

Irinotecan Hydrochloride Injection, USP must be diluted prior to infusion. Irinotecan Hydrochloride Injection, USP should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL. Other drugs should not be added to the infusion solution.

The solution is physically and chemically stable for up to 24 hours at room temperature and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing Irinotecan Hydrochloride Injection, USP and admixtures of Irinotecan Hydrochloride Injection, USP may result in precipitation of the drug and should be avoided.

The Irinotecan Hydrochloride Injection, USP solution should be used immediately after reconstitution as it contains no antibacterial preservative. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 4 hours if kept at room temperature. If reconstitution and dilution are performed under strict aseptic conditions (e.g. on Laminar Air Flow bench), Irinotecan Hydrochloride Injection, USP solution should be used (infusion completed) within 12 hours at room temperature or 24 hours if refrigerated (2° to 8°C, 36° to 46°F).

Safe Handling
Care should be exercised in the handling and preparation of infusion solutions prepared from Irinotecan Hydrochloride Injection, USP. The use of gloves is recommended. If a solution of Irinotecan Hydrochloride Injection, USP contacts the skin, wash the skin immediately and thoroughly with soap and water. If Irinotecan Hydrochloride Injection, USP contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.

Extravasation
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 applications of ice are recommended.

DOSAGE FORMS AND STRENGTHS

Irinotecan Hydrochloride Injection, USP is available in three 20 mg/mL single-dose sizes:

  • 2 mL-fill vial containing 40 mg irinotecan hydrochloride
  • 5 mL-fill vial containing 100 mg irinotecan hydrochloride
  • 25 mL-fill vial containing 500 mg irinotecan hydrochloride
CONTRAINDICATIONS
  • Irinotecan Hydrochloride Injection, USP is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
WARNINGS AND PRECAUTIONS

Diarrhea and Cholinergic Reactions
Early diarrhea (occurring during or shortly after infusion of Irinotecan Hydrochloride Injection, USP) is usually transient and infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Bradycardia may also occur. Early diarrhea and other cholinergic symptoms may be prevented or treated. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). These symptoms are expected to occur more frequently with higher irinotecan doses.

Late diarrhea (generally occurring more than 24 hours after administration of Irinotecan Hydrochloride Injection, USP) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Grade 3-4 late diarrhea occurred in 23-31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. One dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication. Patients must not be treated with irinotecan until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of Irinotecan Hydrochloride Injection, USP should be decreased.

Avoid diuretics or laxatives in patients with diarrhea.

Myelosuppression
Deaths due to sepsis following severe neutropenia have been reported in patients treated with Irinotecan Hydrochloride Injection, USP. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia. Manage febrile neutropenia promptly with antibiotic support. Hold Irinotecan Hydrochloride Injection, USP if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm3. After recovery to an absolute neutrophil count ≥1000/mm3, subsequent doses of Irinotecan Hydrochloride Injection, USP should be reduced.

When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation (48% [13/27] versus 24% [67/277]; p=0.04). Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of Irinotecan Hydrochloride Injection, USP. Based on sparse available data, the concurrent administration of Irinotecan Hydrochloride Injection, USP with irradiation is not recommended.

Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/266]; p<0.001). Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may be at greater risk of myelosuppression when receiving therapy with Irinotecan Hydrochloride Injection, USP.

Patients With Reduced UGT1A1 Activity
Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of Irinotecan Hydrochloride Injection, USP treatment.

In a study of 66 patients who received single-agent Irinotecan Hydrochloride Injection, USP (350 mg/m2 once-every-3-weeks), the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50%, and in patients heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%. No grade 4 neutropenia was observed in patients homozygous for the wild-type allele (UGT1A1 6/6 genotype).

When administered as a single-agent, a reduction in the starting dose by at least one level of Irinotecan Hydrochloride Injection, USP should be considered for patients known to be homozygous for the UGT1A1*28 allele. 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.

Hypersensitivity
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue Irinotecan Hydrochloride Injection, USP if anaphylactic reaction occurs.

Renal Impairment/Renal Failure
Renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea.

Pulmonary Toxicity
Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred in patients receiving irinotecan (as monotherapy). Risk factors include preexisting 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. In Japanese studies, a reticulonodular pattern on chest x-ray was observed in a small percentage of patients. New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation. If IPD is diagnosed, irinotecan and other chemotherapy should be discontinued and appropriate treatment instituted as needed.

Toxicity of the 5 Day Regimen
Outside of a well-designed clinical study, Irinotecan Hydrochloride Injection, USP should not be used in combination with a regimen of 5-FU/LV administered for 4-5 consecutive days every 4 weeks because of reports of increased toxicity, including toxic deaths. Irinotecan Hydrochloride Injection, USP should be used as recommended.

Increased Toxicity in Patients with Performance Status 2
In the clinical trials, higher rates of hospitalization, 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.

Pregnancy
Irinotecan Hydrochloride Injection, USP can cause fetal harm when administered to a pregnant woman. Irinotecan was embryotoxic in rats and rabbits at doses significantly lower than those administered to humans on a mg/m2 basis. In rats, at exposures approximately 0.2 times those achieved in humans at the 125 mg/m2 dose, irinotecan was embryotoxic and resulted in decreased learning ability and female fetal body weight in surviving pups; the drug was teratogenic at lower exposures (approximately 0.025 times the AUC in humans at the 125 mg/m2 dose).There are no adequate and well-controlled studies of irinotecan in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Irinotecan Hydrochloride Injection, USP.

Patients with Hepatic Impairment
The use of Irinotecan Hydrochloride Injection, USP in patients with significant hepatic impairment has not been established. In clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin >2.0 mg/dL, 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. In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first-cycle, grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/226]; p<0.001).

ADVERSE REACTIONS

Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common adverse reactions (>30%) observed in single agent therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and alopecia.

Serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia.

Second-Line Single-Agent Therapy
Weekly Dosage Schedule

In three clinical studies evaluating the weekly dosage schedule, 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5-FU-based therapy were treated with Irinotecan Hydrochloride Injection, USP. Seventeen of the patients died within 30 days of the administration of Irinotecan Hydrochloride Injection, USP; in five cases (1.6%, 5/304), the deaths were potentially drug-related. One of the patients died of neutropenic sepsis without fever. Neutropenic fever occurred in nine (3.0%) other patients; these patients recovered with supportive care.

One hundred nineteen (39.1%) of the 304 patients were hospitalized because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be related to administration of Irinotecan Hydrochloride Injection, USP. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea and/or vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever (8.2%); and nausea and/or vomiting (4.9%).

The first dose of at least one cycle of Irinotecan Hydrochloride Injection, USP was reduced for 67% of patients who began the studies at the 125-mg/m2 starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m2 dose level. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with Irinotecan Hydrochloride Injection, USP because of adverse events. The adverse events in Table 3 are based on the experience of the 304 patients enrolled in the three studies described in CLINICAL STUDIES.

Table 3. Adverse Events Occurring in >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectuma
Body System & Event % of Patients Reporting
NCI Grades 1-4 NCI Grades 3 & 4
GASTROINTESTINAL
     Diarrhea (late)b
         7-9 stools/day (grade 3)
         ≥10 stools/day (grade 4)
     Nausea
     Vomiting
     Anorexia
     Diarrhea (early)c
     Constipation
     Flatulence
     Stomatitis
     Dyspepsia
 
88


86
67
55
51
30
12
12
10
 
31
(16)
(14)
17
12
6
8
2
0
1
0
HEMATOLOGIC
     Leukopenia
     Anemia
     Neutropenia
         500 to <1000/mm3 (grade 3)
         <500/mm3 (grade 4)
 
63
60
54

 
28
7
26
(15)
(12)
BODY AS A WHOLE
     Asthenia
     Abdominal cramping/pain
     Fever
     Pain
     Headache
     Back pain
     Chills
     Minor infectiond
     Edema
     Abdominal enlargement
 
76
57
45
24
17
14
14
14
10
10
 
12
16
1
2
1
2
0
0
1
0
METABOLIC AND NUTRITIONAL
     ↓ Body weight
     Dehydration
     ↑ Alkaline phosphatase
     ↑ SGOT
 
30
15
13
10
 
1
4
4
1
DERMATOLOGIC
     Alopecia
     Sweating
     Rash
 
60
16
13
 
NAe
0
1
RESPIRATORY
     Dyspnea
     ↑ Coughing
     Rhinitis
 
22
17
16
 
4
0
0
NEUROLOGIC
     Insomnia
     Dizziness
 
19
15
 
0
0
CARDIOVASCULAR
     Vasodilation (flushing)
 
11
 
0
a   Severity of adverse events based on NCI CTC (version 1.0)
b   Occurring >24 hours after administration of Irinotecan Hydrochloride Injection, USP
c   Occurring ≤24 hours after administration of Irinotecan Hydrochloride Injection, USP
d    Primarily upper respiratory infections
e   Not applicable; complete hair loss = NCI grade 2

Once-Every-3-Week Dosage Schedule
A total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days of treatment. In three cases (1%, 3/316), the deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. One (0.8%, 1/129) patient treated with 5-FU died within 30 days of treatment; this death was attributed to grade 4 diarrhea.

Hospitalizations due to serious adverse events occurred at least once in 60% (188/316) of patients who received irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129) who received 5-FU-based therapy. Eight percent of patients treated with irinotecan and 7% treated with 5-FU-based therapy discontinued treatment due to adverse events.

Of the 316 patients treated with irinotecan, the most clinically significant adverse events (all grades, 1-4) were diarrhea (84%), alopecia (72%), nausea (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). Table 4 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 (14.1).

Table 4. Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Comparative Studies Of Once-Every-3-Week Irinotecan Therapya
Adverse Event Study 1 Study 2
Irinotecan
N = 189
BSCb
N = 90
Irinotecan
N = 127
5-FU
N = 129
TOTAL Grade 3/4 Adverse Events79676954
GASTROINTESTINAL
     Diarrhea
     Vomiting
     Nausea
     Abdominal pain
     Constipation
     Anorexia
     Mucositis
 
22
14
14
14
10
5
2
 
6
8
3
16
8
7
1
 
22
14
11
9
8
6
2
 
11
5
4
8
6
4
5
HEMATOLOGIC
     Leukopenia/Neutropenia
     Anemia
     Hemorrhage
     Thrombocytopenia
Infection
     without grade 3/4 neutropenia
     with grade 3/4 neutropenia
Fever
     without grade 3/4 neutropenia
     with grade 3/4 neutropenia
 
22
7
5
1
 
8
1
 
2
2
 
0
6
3
0
 
3
0
 
1
0
 
14
6
1
4
 
1
2
 
2
4
 
2
3
3
2
 
4
0
 
0
2
BODY AS A WHOLE
     Pain
     Asthenia
 
19
15
 
22
19
 
17
13
 
13
12
METABOLIC AND NUTRITIONAL
     Hepaticc
 
9
 
7
 
9
 
6
DERMATOLOGIC
     Hand and foot syndrome
     Cutaneous signsd 
 
0
2
 
0
0
 
0
1
 
5
3
RESPIRATORYe 10857
NEUROLOGICf121394
CARDIOVASCULARg9342
OTHERh32281214
a          Severity of adverse events based on NCI CTC (version 1.0)
b       BSC = best supportive care
c       Hepatic includes events such as ascites and jaundice
d       Cutaneous signs include events such as rash
e       Respiratory includes events such as dyspnea and cough
f           Neurologic includes events such as somnolence
g       Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction
h          Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss

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

Postmarketing Experience
The following adverse reactions have been identified during post approval use of Irinotecan Hydrochloride Injection, USP. 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 therapy. Thromboembolic events have been observed in patients receiving Irinotecan Hydrochloride Injection, USP.

Symptomatic pancreatitis, asymptomatic pancreatic enzyme elevation have been reported. Increases in serum levels of transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis have been observed.

Hyponatremia, mostly with diarrhea and vomiting, has been reported.

Transient dysarthria has been reported in patients treated with Irinotecan Hydrochloride Injection, USP; 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.

DRUG INTERACTIONS

Strong CYP 3 A4 Inducers
Anticonvulsants and other strong inducers: Exposure to irinotecan and its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital or carbamazepine. The appropriate starting dose for patients taking these anticonvulsants or other strong inducers such as rifampin and rifabutin has not been defined. Consideration should be given to substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan therapy.

St. John’s wort: Exposure to the active metabolite SN-38 is reduced in patients receiving concomitant St. John’s wort. St. John’s wort should be discontinued at least 2 weeks prior to the first cycle of irinotecan, and St. John’s wort is contraindicated during irinotecan therapy.

Dexamethasone, a moderate CYP3A4 inducer, does not appear to alter the pharmacokinetics of irinotecan.

Strong CYP 3 A4 Inhibitors
Ketoconazole is a strong inhibitor of CYP3A4 enzymes. Patients receiving concomitant ketoconazole have increased exposure to irinotecan and its active metabolite SN-38. Patients should discontinue ketoconazole at least 1 week prior to starting irinotecan therapy and ketoconazole is contraindicated during irinotecan therapy.

Atazanavir Sulfate
Coadministration 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.

Drug-Laboratory Test Interactions
There are no known interactions between Irinotecan Hydrochloride Injection, USP and laboratory tests.

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category D [see Warnings and Precautions]

Irinotecan Hydrochloride Injection, USP can cause fetal harm when administered to a pregnant woman. Radioactivity related to 14C-irinotecan crosses the placenta of rats following intravenous administration of 10 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about 3 and 0.5 times, respectively, the corresponding values in patients administered 125 mg/m2). Intravenous administration of irinotecan 6 mg/kg/day to rats and rabbits during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses. In separate studies in rats, this dose produced an irinotecan Cmax and AUC of about 2 and 0.2 times, respectively, the corresponding values in patients administered 125 mg/m2. In rabbits, the embryotoxic dose was about one-half the recommended human weekly starting dose on a mg/m2 basis. Irinotecan was teratogenic in rats at doses greater than 1.2 mg/kg/day and in rabbits at 6.0 mg/kg/day. In separate studies in rats, this dose produced an irinotecan Cmax and AUC about 2/3 and 1/40th, respectively, of the corresponding values in patients administered 125 mg/m2. In rabbits, the teratogenic dose was about one-half the recommended human weekly starting dose on a mg/m2 basis. Teratogenic effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring. There are no adequate and well-controlled studies of irinotecan in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Irinotecan Hydrochloride Injection, USP.

Nursing Mothers
Radioactivity appeared in rat 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 this drug 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 from Irinotecan Hydrochloride Injection, USP, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use
The effectiveness of irinotecan in pediatric patients has not been established. Results from two open-label, single arm studies were evaluated. One hundred and seventy children with refractory solid tumors were enrolled in one phase 2 trial in which 50 mg/m2 of irinotecan was infused for 5 consecutive days every 3 weeks. Grade 3-4 neutropenia was experienced by 54 (31.8%) patients. Neutropenia was complicated by fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35 (20.6%) patients. This adverse event profile was comparable to that observed in adults. In the second phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m2 of irinotecan was infused for 5 consecutive days on weeks 0, 1, 3 and 4. This single agent therapy was followed by multimodal therapy. Accrual to the single agent irinotecan phase was halted due to the high rate (28.6%) of progressive disease and the early deaths (14%). 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 (28.6%) associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%) (across all courses of therapy and irrespective of causal relationship).

Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric solid-tumor trials at dose levels of 50 mg/m2 (60-min infusion, n=48) and 125 mg/m2 (90-min infusion, n=6). Irinotecan clearance (mean ± S.D.) was 17.3 ± 6.7 L/h/m2 for the 50 mg/m2 dose and 16.2 ± 4.6 L/h/m2 for the 125 mg/m2 dose, which is comparable to that in adults. Dose-normalized SN-38 AUC values were comparable between adults and children. Minimal accumulation of irinotecan and SN-38 was observed in children on daily dosing regimens [daily x 5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks].

Geriatric Use
Patients greater than 65 years of age should be closely monitored because of a greater risk of early and late diarrhea in this population. The starting dose of Irinotecan Hydrochloride Injection, USP in patients 70 years and older for the once-every-3-week-dosage schedule should be 300 mg/m2 .

The frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients ≥65 years than in patients <65 years (40% [53/133] versus 23% [40/171]; p=0.002). In another study of 183 patients treated on the weekly schedule, the frequency of grade 3 or 4 late diarrhea in patients ≥65 years of age was 28.6% [26/91] and in patients <65 years of age was 23.9% [22/92].

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 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-38 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 in patients with hepatic impairment. The tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently, and no recommendations for dosing can be made.

OVERDOSAGE

In U.S. phase 1 trials, single doses of up to 345 mg/m2 of irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/m2 of irinotecan have been given in non-U.S. trials. 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, USP. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.

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 0.9 mg of lactic acid, USP and Water for Injection, USP. The pH of the solution has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan Hydrochloride Injection, USP is intended for dilution with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion. The preferred diluent is 5% Dextrose Injection, USP.

Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extract from plants such as Camptotheca acuminata or is chemically synthesized.

The chemical name is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1Hpyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4’bipiperidine]-1’-carboxylate, monohydrochloride, trihydrate. Its empirical formula is C33H38N4O6•HCl•3H2O and molecular weight is 677.19. It is slightly soluble in water and organic solvents. Its structural formula is as follows:

Irinotecan Hydrochloride structural formula

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-38 bind to the topoisomerase IDNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan 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 or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.

Pharmacodynamics
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold; however, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan. The precise contribution of SN38 to the activity of Irinotecan Hydrochloride Injection, USP is thus unknown. Both irinotecan and SN-38 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-38 is about 10 to 20 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium.

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. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan. Pharmacokinetic parameters for irinotecan and SN-38 following a 90-minute infusion of irinotecan at dose levels of 125 and 340 mg/m2 determined in two clinical studies in patients with solid tumors are summarized in Table 5:

Table 5. Summary of Mean (±Standard Deviation) Irinotecan and SN-38 Pharmacokinetic Parameters in Patients with Solid Tumors
Dose (mg/m2) Irinotecan SN-38
Cmax (ng/mL) AUC0-24 (ng·h/mL) t1/2
(h)
Vz
(L/m2)
CL
(L/h/m2)
Cmax (ng/mL) AUC0-24 (ng·h/mL) t1/2
(h)
125
(N = 64)
1,660
±797
10,200
±3,270
5.8a
±0.7
110
±48.5
13.3
±6.01
26.3
±11.9
229
±108
10.4a
±3.1
340
(N = 6)
3,392
±874
20,604
±6,027
11.7b
±1.0
234
±69.6
13.9
±4.0
56.0
±28.2
474
±245
21.0b
±4.3
Cmax - Maximum plasma concentration
AUC0-24 - Area under the plasma concentration-time curve from time 0 to 24 hours after the end of the 90-minute infusion
t1/2 - Terminal elimination half-life
Vz - 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 and SN-38.

Distribution
Irinotecan 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 and SN-38 predominantly binds is albumin.

Metabolism
The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in the liver. In vitro studies indicate that irinotecan, SN-38 and another metabolite aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 isozymes. SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype). In a prospective study, in which irinotecan was administered as a single-agent (350 mg/m2) on a once-every-3-week schedule, patients with the UGT1A1 7/7 genotype had a higher exposure to SN-38 than patients with the wild-type UGT1A1 allele (UGT1A1 6/6 genotype). SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity assays using two cell lines in vitro.

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

Effect of Age
The pharmacokinetics of irinotecan administered using the weekly schedule was evaluated in a study of 183 patients that was prospectively designed to investigate the effect of age on irinotecan toxicity. Results from this trial indicate that there are no differences in the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide in patients <65 years of age compared with patients ≥65 years of age. In a study of 162 patients that was not prospectively designed to investigate the effect of age, small (less than 18%) but statistically significant differences in dose-normalized irinotecan pharmacokinetic parameters in patients <65 years of age compared to patients ≥65 years of age were observed. Although dose-normalized AUC0-24 for SN-38 in patients ≥65 years of age was 11% higher than in patients <65 years of age, this difference was not statistically significant. No change in the starting dose is recommended for geriatric patients receiving the weekly dosage schedule of irinotecan.

Effect of Gender
The pharmacokinetics of irinotecan do not appear to be influenced by gender.

Effect of Race
The influence of race on the pharmacokinetics of irinotecan has not been evaluated.

Effect of Hepatic Impairment
Irinotecan clearance is diminished in patients with hepatic impairment while exposure to the active metabolite SN-38 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. However, the tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently.

Effect of Renal Impairment
The influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated. Therefore, caution should be undertaken in patients with impaired renal function. Irinotecan is not recommended for use in patients on dialysis.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan Cmax and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/m2 weekly) 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 was clastogenic both in vitro chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan nor its active metabolite SN-38 was mutagenic in the in vitro Ames assay.

No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to rats and rabbits; however, atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg and in dogs at 0.4 mg/kg. In separate studies in rodents, this dose produced an irinotecan Cmax and AUC about 5 and 1 times, respectively, of the corresponding values in patients administered 125 mg/m2 weekly. In dogs this dose produced an irinotecan Cmax and AUC about one-half and 1/15th, respectively, of the corresponding values in patients administered 125 mg/m2 weekly.

CLINICAL STUDIES

Irinotecan has been studied in clinical trials as a single agent. Weekly and once-every-3-week dosage schedules were used for the single-agent irinotecan studies. Clinical studies of single-agent use are described below.

Metastatic Colorectal Cancer

Second-Line Therapy After 5-FU-Based Treatment
4 Weekly Doses on a 6-Week Cycle: Studies 3, 4, and 5
Data from three open-label, single-agent, clinical studies, involving a total of 304 patients in 59 centers, support the use of Irinotecan Hydrochloride Injection, USP 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. These studies were designed to evaluate tumor response rate and do not provide information on effects on survival and disease-related symptoms. In each study, Irinotecan Hydrochloride Injection, USP was administered in repeated 6-week cycles consisting of a 90-minute intravenous infusion once weekly for 4 weeks, followed by a 2-week rest period. Starting doses of Irinotecan Hydrochloride Injection, USP in these trials were 100, 125, or 150 mg/m2, but the 150-mg/m2 dose was poorly tolerated (due to high rates of grade 4 late diarrhea and febrile neutropenia). Study 3 enrolled 48 patients and was conducted by a single investigator at several regional hospitals. Study 4 was a multicenter study conducted by the North Central Cancer Treatment Group. All 90 patients enrolled in Study 4 received a starting dose of 125 mg/m2. Study 5 was a multicenter study that enrolled 166 patients from 30 institutions. The initial dose in Study 5 was 125 mg/m2 but was reduced to 100 mg/m2 because the toxicity seen at the 125 mg/m2 dose was perceived to be greater than that seen in previous studies. All patients in these studies had metastatic colorectal cancer, and the majority had disease that recurred or progressed following a 5-FU-based regimen administered for metastatic disease. The results of the individual studies are shown in Table 6.

Table 6. Weekly Dosage Schedule: Study Results
Study
345
Number of Patients489064102
Starting Dose (mg/m2/wk x 4) 125a125125100
Demographics and Treatment Administration
Female/Male (%) 46/5436/6450/5051/49
Median Age in years (range)63 (29-78)63 (32-81)61 (42-84)64 (25-84)
Ethnic Origin (%)
    White
    African American
    Hispanic
    Oriental/Asian
 
79
12
8
0
 
96
4
0
0
 
81
11
8
0
 
91
5
2
2
Performance Status (%)
    0
    1
    2
 
60
38
2
 
38
48
14
 
59
33
8
 
44
51
5
Primary Tumor (%)
    Colon
    Rectum
    Unknown
 
100
0
0
 
71
29
0
 
89
11
0
 
87
8
5
Prior 5-FU Therapy (%)
    For Metastatic Disease
    ≤6 months after Adjuvant
    >6 months after Adjuvant
    Classification Unknown
 
81
15
2
2
 
66
7
16
12
 73
27
0
0
 
68
28
2
3
Prior Pelvic/Abdominal Irradiation (%)
    Yes
    Other
    None
 
3
0
97
 
29
9
62
 
0
2
98
 
0
4
96
Duration of Treatment with Irinotecan Hydrochloride Injection, USP (median, months)5443
Relative Dose Intensityb (median %) 74677381
Efficacy
Confirmed Objective Response Rate (%)c (95% CI)21
(9.3 - 32.3)
13
(6.3 - 20.4)
14
(5.5 - 22.6)
9
(3.3 - 14.3)
Time to Response (median, months) 2.61.52.82.8
Response Duration (median, months) 6.45.95.66.4
Survival (median, months) 10.48.110.79.3
1-Year Survival (%) 46314543
a       Nine patients received 150 mg/m2 as a starting dose; two (22.2%) responded to Irinotecan Hydrochloride Injection.
b          Relative dose intensity for Irinotecan Hydrochloride Injection 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.
c       Confirmed ≥4 to 6 weeks after first evidence of objective response.

In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m2. Among these 193 patients, 2 complete and 27 partial responses were observed, for an overall response rate of 15.0% (95% Confidence Interval [CI], 10.0% to 20.1%) at this starting dose. A considerably lower response rate was seen with a starting dose of 100 mg/m2. The majority of responses were observed within the first two cycles of therapy, but responses did occur in later cycles of treatment (one response was observed after the eighth cycle). The median response duration for patients beginning therapy at 125 mg/m2 was 5.8 months (range, 2.6 to 15.1 months). Of the 304 patients treated in the three studies, response rates to Irinotecan Hydrochloride Injection, USP were similar in males and females and among patients older and 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. The response rate was 18.5% in patients with a performance status of 0 and 8.2% in patients with a performance status of 1 or 2. Patients with a performance status of 3 or 4 have not been studied. Over half of the patients responding to Irinotecan Hydrochloride Injection, USP had not responded to prior 5-FU. Patients who had received previous irradiation to the pelvis responded to Irinotecan Hydrochloride Injection, USP at approximately the same rate as those who had not previously received irradiation.

Once-Every-3-Week Dosage Schedule
Single Arm Study: Study 6
Data from an open-label, single-agent, single-arm, multicenter, clinical study involving a total of 132 patients support a once every-3-week dosage schedule of irinotecan in the treatment of patients with metastatic cancer of the colon or rectum that recurred or progressed following treatment with 5-FU. Patients received a starting dose of 350 mg/m2 given by 30-minute intravenous infusion once every 3 weeks. Among the 132 previously treated patients in this trial, the intent-to-treat response rate was 12.1% (95% CI, 7.0% to 18.1%).

Randomized Studies: Studies 7 and 8
Two multicenter, randomized, clinical studies further support the use of irinotecan given by the once-every-3-week dosage schedule in patients with metastatic colorectal cancer whose disease has recurred or progressed following prior 5-FU therapy. In Study 7, second-line irinotecan therapy plus best supportive care was compared with best supportive care alone. In Study 8, second-line irinotecan therapy was compared with infusional 5-FU-based therapy. In both studies, irinotecan was administered intravenously at a starting dose of 350 mg/m2 over 90 minutes once every 3 weeks. The starting dose was 300 mg/m2 for patients who were 70 years and older or who had a performance status of 2. The highest total dose permitted was 700 mg. Dose reductions and/or administration delays were permitted in the event of severe hematologic and/or nonhematologic toxicities while on treatment. Best supportive care was provided to patients in both arms of Study 7 and included antibiotics, analgesics, corticosteroids, transfusions, psychotherapy, or any other symptomatic therapy as clinically indicated. In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. If late diarrhea persisted for greater than 24 hours despite loperamide, a 7-day course of fluoroquinolone antibiotic prophylaxis was given. Patients in the control arm of the Study 8 received one of the following 5-FU regimens: (1) LV, 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; (2) 5-FU, 250 to 300 mg/m2/day protracted continuous IV infusion until toxicity; (3) 5FU, 2.6 to 3 g/m2 IV over 24 hours every week for 6 weeks with or without LV, 20 to 500 mg/m2/day every week IV for 6 weeks with 2-week rest between cycles. Patients were to be followed every 3 to 6 weeks for 1 year.

A total of 535 patients were randomized in the two studies at 94 centers. The primary endpoint in both studies was survival. The studies demonstrated a significant overall survival advantage for irinotecan compared with best supportive care (p=0.0001) and infusional 5-FU-based therapy (p=0.035) as shown in Figures 1 and 2. In Study 7, median survival for patients treated with irinotecan was 9.2 months compared with 6.5 months for patients receiving best supportive care. In Study 8, median survival for patients treated with irinotecan was 10.8 months compared with 8.5 months for patients receiving infusional 5‑FU-based therapy. Multiple regression analyses determined that patients’ baseline characteristics also had a significant effect on survival. When adjusted for performance status and other baseline prognostic factors, survival among patients treated with irinotecan remained significantly longer than in the control populations (p=0.001 for Study 7 and p=0.017 for Study 8). Measurements of pain, performance status, and weight loss were collected prospectively in the two studies; however, the plan for the analysis of these data was defined retrospectively. When comparing irinotecan with best supportive care in Study 7, this analysis showed a statistically significant advantage for irinotecan, with longer time to development of pain (6.9 months versus 2.0 months), time to performance status deterioration (5.7 months versus 3.3 months), and time to >5% weight loss (6.4 months versus 4.2 months). Additionally, 33.3% (33/99) of patients with a baseline performance status of 1 or 2 showed an improvement in performance status when treated with irinotecan versus 11.3% (7/62) of patients receiving best supportive care (p=0.002). Because of the inclusion of patients with non-measurable disease, intent-to-treat response rates could not be assessed.

 Figure 1. Survival Second-Line Irinotecan vs Best Supportive Care (BSC) Study 7

 Figure 2. Survival Second-Line Irinotecan vs Infusional 5-FU Study 8

Table 7. Once-Every-3-Week Dosage Schedule: Study Results
Study 7 Study 8
IrinotecanBSCaIrinotecan5-FU
Number of Patients18990127129
Demographics and Treatment Administration
Female/Male (%) 32/6842/5843/5735/65
Median age in years (range) 59 (22-75)62 (34-75)58 (30-75)58 (25-75)
Performance status (%)
     0
     1
     2
 
47
39
14
 
31
46
23
 
58
35
8
 
54
43
3
Primary tumor (%)
     Colon
     Rectum
 
55
45
 
52
48
 
57
43
 
62
38
Prior 5-FU therapy (%)
     For metastatic disease
     As adjuvant treatment
 
70
30
 
63
37
 
58
42
 
68
32
Prior irradiation (%) 26271820
Duration of study treatment (median, months)
(Log-rank test)
4.14.2
(p = 0.02)
2.8
Relative dose intensity (median %)b 949581-99
Survival
Survival (median, months)
(Log-rank test)
9.2
(p = 0.0001)
6.510.8
(p = 0.035)
8.5
a       BSC = best supportive care
b       Relative dose intensity for irinotecan based on planned dose intensity of 116.7 and 100 mg/m2/wk corresponding with 350 and 300 mg/m2 starting doses, respectively.

In the two randomized studies, the EORTC QLQ-C30 instrument was utilized. At the start of each cycle of therapy, patients completed a questionnaire consisting of 30 questions, such as “Did pain interfere with daily activities?” (1 = Not at All, to 4 = Very Much) and “Do you have any trouble taking a long walk?” (Yes or No). The answers from the 30 questions were converted into 15 subscales, that were scored from 0 to 100, and the global health status subscale that was derived from two questions about the patient’s sense of general well being in the past week. The results as summarized in Table 13 are based on patients’ worst post-baseline scores. In Study 7, a multivariate analysis and univariate analyses of the individual subscales were performed and corrected for multivariate testing. Patients receiving irinotecan reported significantly better results for the global health status, on two of five functional subscales, and on four of nine symptom subscales. As expected, patients receiving irinotecan noted significantly more diarrhea than those receiving best supportive care. In Study 8, the multivariate analysis on all 15 subscales did not indicate a statistically significant difference between irinotecan and infusional 5-FU.

Table 8. EORTC QLQ-C30: Mean Worst Post-Baseline Scorea
QLQ-C30 Subscale Study 7 Study 8
Irinotecan BSC p-value Irinotecan 5-FU p-value
Global Health Status47370.0353520.9
Functional Scales
Cognitive 77680.0779830.9
Emotional 68640.464680.9
Social 58470.0665670.9
Physical 60400.000366660.9
Role 53350.0254570.9
Symptom Scales
Fatigue 51630.0347460.9
Appetite loss 37570.000735380.9
Pain assessment 41560.00938340.9
Insomnia 39470.339330.9
Constipation 28410.0325190.9
Dyspnea 31400.225240.9
Nausea/Vomiting 27290.525160.09
Financial impact 22260.524150.3
Diarrhea 32190.0132220.2
a       For the five functional subscales and global health status subscale, higher scores imply better functioning, whereas, on the nine symptom subscales, higher scores imply more severe symptoms. The subscale scores of each patient were collected at each visit until the patient dropped out of the study.
REFERENCES
  • NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
  • OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.
    http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
  • American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
  • Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.
16 HOW SUPPLIED/STORAGE AND HANDLING

Each mL of Irinotecan Hydrochloride Injection, USP contains 20 mg irinotecan (on the basis of the trihydrate salt); 45 mg sorbitol; 0.9 mg of lactic acid, USP and Water for Injection, USP. When necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid.

Irinotecan Hydrochloride Injection, USP is available in single-dose amber glass vials in the following package size:

40 mg/2 mL (20 mg/mL)
100 mg/5 mL (20 mg/mL)
500 mg/25 mL (20 mg/mL)

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

Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from light. Keep the vial in the carton until the time of use.

Inspect the vial for damage and visible signs of leaks before removing from the carton. If damaged, incinerate the unopened package.

PATIENT COUNSELING INFORMATION
  • Patients and caregivers should be informed of gastrointestinal complications, such as nausea, vomiting, abdominal cramping, and diarrhea. Patients should have loperamide readily available to begin treatment for late diarrhea (generally occurring more than 24 hours after administration of Irinotecan Hydrochloride Injection, USP). Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. One dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Patients should contact their physician if any of the following occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to get diarrhea under control within 24 hours.
  • Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of Irinotecan Hydrochloride Injection, USP.
  • Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever or infection.
  • Irinotecan Hydrochloride Injection, USP may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug.
  • Patients should be alerted to the possibility of alopecia.
  • Contains sorbitol.

Irinotecan
Generic Name
Irinotecan
Generic Name
Irinotecan
Generic Name
Irinotecan
Generic Name
Irinotecan
Generic Name
Irinotecan
Generic Name
Irinotecan
Description

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