Gemcitabine Hydrochloride
200mg Injection

What is in this leaflet?

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

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Gemcitabine for Injection against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet.
You may need to read it again

What Gemcitabine for Injection is used for

This medicine is used to treat the following types of cancer:

• lung cancer
• pancreatic cancer
• bladder cancer
• breast cancer
• ovarian cancer.

This medicine belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.
This medicine works by killing cancer cells and stopping cancer cells from growing and multiplying.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.
Gemcitabine for Injection may be used alone or in combination with other medicines to treat cancer. This medicine is not addictive.

This medicine is available only with a doctor’s prescription.

Before you are given Gemcitabine for Injection

When you must not be given it
You must not be given Gemcitabine for Injection if you have an allergy to:

• any medicine containing Gemcitabine hydrochloride
• any of the ingredients listed at the end of this leaflet
• if the packaging is torn or shows sign of tampering.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching, or hives on the skin.

Tell your doctor or pharmacist if you are pregnant or intend to become pregnant.

Like most cytotoxic medicines, Gemcitabine for Injection is not recommended for use during pregnancy. If there is any need to consider Gemcitabine for Injection during your pregnancy, your doctor or pharmacist will discuss with you the benefits and risks of using it.

Gemcitabine for Injection may cause birth defects if either the male or female is using it at the time of conception. It is recommended that you use some kind of birth control while you are being treated with  Gemcitabine for Injection.

Tell your doctor or pharmacist if you are breast-feeding while being treated with this medicine.
Gemcitabine for Injection may pass into breast milk and there is a possibility that your baby may be affected.

You must not be given this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.
If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it
Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes Tell your doctor if you have or have had any medical conditions, especially the following:

• liver problems
• kidney problems.

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

Taking other medicines

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

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

Your doctor and pharmacist have more information on medicines to be careful with or avoid while you are being treated with this medicine.

How Gemcitabine for Injection is given

How much is given
Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight, liver function, kidney function and other chemotherapy medicines you are being given.

Gemcitabine for Injection may be given alone or in combination with other drugs.

Several courses of Gemcitabine for Injection therapy may be needed depending on your response to treatment. Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any uncontrolled effects have been controlled

Ask your doctor if you want to know more about the dose of Gemcitabine for Injection you receive.

How it is given
Gemcitabine for Injection must only be given by a doctor or nurse.
This medicine is usually given as a slow injection into a vein over 30 minutes.

How often is it given

For Lung Cancer
Gemcitabine for Injection can be given once a week for three consecutive weeks, followed by one week without treatment or once a week for two consecutive weeks, followed by one week without treatment. Your doctor will decide how many of these cycles you will need

For Pancreatic Cancer
Initially, Gemcitabine for Injection is given once a week for up to seven weeks followed by a week without treatment. Subsequent cycles of Gemcitabine for Injection are given once a week for three consecutive weeks followed by a week without treatment. Your doctor will decide how many of these cycles you will need.

For Bladder Cancer
Gemcitabine for Injection is given once a week for three consecutive weeks, followed by one week without treatment. Your doctor will decide how many of these cycles you will need

For Breast Cancer.
Gemcitabine for Injection is given once a week for two consecutive weeks, followed by one week without treatment. Your doctor will decide how many of these cycles you will need.

For Ovarian Cancer
Gemcitabine for Injection can be given once a week for two consecutive weeks, followed by one week without treatment. Your doctor will decide how many of these cycles you will need.

If you take too much (overdose)

As Gemcitabine for Injection is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience any severe side effects after being given Gemcitabine for Injection, tell your doctor immediately or go to Accident and Emergency at the nearest hospital.

In case of overdose, immediately contact the Poisons Information Centre for advice.
You may need urgent medical attention

While you are being treated with Gemcitabine for Injection

Things you must do

If you are about to be started on any new medicine,  remind your doctor and pharmacist that you are being given Gemcitabine for Injection.

Tell any other doctors, dentists and pharmacists who treat you that you are being given this medicine
If you become pregnant while being given this medicine, or soon after, tell your doctor immediately.

Keep all your doctor’s appointments so your progress can be checked.
Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and to detect any unwanted side effects.

Keep follow up appointments with your doctor.
It is important to have your follow-up doses of  Gemcitabine for Injection at the appropriate times to get the best effects from your treatments.

Things to be careful of

Be careful driving or operating machinery until you know how Gemcitabine for Injection affects you.
This medicine may cause sleepiness or drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery, or do anything else that could be dangerous.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being treated with Gemcitabine for Injection.

Like other medicines that treat cancer, Gemcitabine for Injection may have unwanted side effects, some of which may be serious. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following lists of side effects.
 You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.
Tell your doctor, nurse or pharmacist if you notice any of the following and they worry you:

• sleepiness, drowsiness
• itchy rash
• swelling of the hands, feet or face
• unusual hair loss or thinning
• soreness in the mouth
• scaling, ulceration, sore formation on the skin
• pain at the site of injection
• itching.

Stomach or bowel problems such as:

• feeling sick
• vomiting
• diarrhoea
• constipation.

Influenza-likesymptomssuchas:

• fever
• headache
• back-pain
• cold shivers
• cough
• sweating
• muscle pain
• unusual tiredness or weakness
• loss of appetite
• generally feeling unwell
• inability to sleep
• runny or blocked nose, sneezing.

Tell your doctor as soon as possible if you notice any of the following side effects:

• frequent infections such as fever, severe chills, sore throat or ulcers
• wheezing or coughing
• bruising or bleeding more easily than normal
• tiredness, headaches, being short of breath when exercising

These may be serious side effects. You may need medical attention.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if any of the following happen:

• sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips or tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
• rapid laboured breathing; extreme shortness of breath; slightly bluish, greyish or dark purple discolouration of the skin; cold extremities
• quick shallow breathing followed by shortness of breath and difficulty in breathing
• bruising or bleeding more easily than normal; yellowing of the skin and/or eyes; passing less urine than is normal
• chest pain, changes in the rhythm or rate of the heart beat.

These are very serious side effects. You may need urgent medical attention or hospitalisation.
Other side effects not listed above may occur in some patients. Tell your doctor or health care professional if you notice anything that is making you feel unwell.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.
Other side effects not listed above may occur in some people. Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

The benefits and side effects of Gemcitabine for Injection may take some time to occur.

Therefore even after you have finished your Gemcitabine for Injection treatment you should tell your doctor immediately if you notice any of the side effects listed in this section.

After using Gemcitabine for Injection

Storage
Gemcitabine for Injection will be stored in the pharmacy or on the ward. The injection should be stored below 25C.

Product Description

What it looks like
Gemcitabine for Injection is a white to off-white powder

Ingredients
Gemcitabine for Injection contains 200mg, 1g or 2g of Gemcitabine hydrochloride as the active ingredient

Inactive ingredients:
It also contains: Mannitol, sodium acetate
This medicine does not contain lactose, sucrose, gluten, tartrazine or any azo dyes

Available Dosage forms:
Gemcitabine for Injection is available in the following strengths:

1. 200 mg/vial
2. 1g/vial
3. 2g/vial

Gemcitabine Hydrochloride
200mg Injection

INDICATIONS AND USAGE

Ovarian Cancer
Gemcitabine for Injection, USP in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

Breast Cancer
Gemcitabine for Injection, USP in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.

Non-Small Cell Lung Cancer
Gemcitabine for Injection, USP is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer.

Pancreatic Cancer
Gemcitabine for Injection, USP is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine for Injection, USP is indicated for patients previously treated with 5-FU.

DOSAGE AND ADMINISTRATION

Ovarian Cancer

Recommended Dose and Schedule
The recommended dose of Gemcitabine for Injection, USP is 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after Gemcitabine for Injection, USP administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information.

Dose Modifications
Recommended Gemcitabine for Injection, USP dose modifications for myelosuppression are described Table 1 and Table 2. Refer to Dosage and Administration for recommendations for non-hematologic adverse reactions.

Breast Cancer

Recommended Dose and Schedule
The recommended dose of Gemcitabine for Injection, USP is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3 hour intravenous infusion before Gemcitabine for Injection, USP administration.

Dose Modifications
Recommended dose modifications for Gemcitabine for Injection, USP for myelosuppression are described in Table 3. Refer to Dosage and Administration for recommendations for non-hematologic adverse reactions.

Non-Small Cell Lung Cancer

Recommended Dose and Schedule
Every 4-week schedule
The recommended dose of Gemcitabine for Injection, USP is 1000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemcitabine for Injection, USP.

Every 3-week schedule
The recommended dose of Gemcitabine for Injection, USP is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemcitabine for Injection, USP.

Dose Modifications
Recommended dose modifications for Gemcitabine for Injection, USP myelosuppression are described in Table 4. Refer to Dosage and Administration for Gemcitabine for Injection, USP recommendations for non-hematologic adverse reactions.

Pancreatic Cancer

Recommended Dose and Schedule
The recommended dose of Gemcitabine for Injection, USP is 1000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule

• Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one week rest.
• After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles.

Dose Modifications
Recommended dose modifications for Gemcitabine for Injection, USP for myelosuppression are described in Table 4. Refer to Dosage and Administration for recommendations for non-hematologic adverse reactions.

Patients receiving Gemcitabine for Injection, USP should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 4.

Dose Modifications for Non-Hematologic Adverse Reactions
Permanently discontinue Gemcitabine for Injection, USP for any of the following

• Unexplained dyspnea or other evidence of severe pulmonary toxicity
• Severe hepatic toxicity
• Hemolytic-Uremic Syndrome
• Capillary Leak Syndrome

Withhold Gemcitabine for Injection, USP or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.

Preparation and Administration Precautions
Exercise caution and wear gloves when preparing Gemcitabine for Injection, USP solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine for Injection, USP contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. For further guidance on handling Gemcitabine for Injection, USP go to “OSHA Hazardous Drugs” (refer to antineoplastic weblinks including OSHA Technical Manual) at OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Preparation for Intravenous Infusion Administration
Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives.

Add 5 mL to the 200-mg vial or 25 mL to the 1-g vial. These dilutions each yield a Gemcitabine for Injection, USP concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg or 1 g of Gemcitabine for Injection, USP. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.

Reconstituted Gemcitabine for Injection, USP is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemcitabine for Injection, USP solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur.

No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

DOSAGE FORMS AND STRENGTHS

Gemcitabine for Injection, USP is a white to off-white lyophilized powder available in sterile single-use vials containing 200 mg or 1 g gemcitabine.

CONTRAINDICATIONS

Gemcitabine for Injection, USP is contraindicated in patients with a known hypersensitivity to gemcitabine.

WARNINGS AND PRECAUTIONS

Schedule-dependent Toxicity
In clinical trials evaluating the maximum tolerated dose of Gemcitabine for Injection, USP, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of Gemcitabine for Injection, USP is influenced by the length of the infusion.

Myelosuppression
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with Gemcitabine for Injection, USP as a single agent and the risks are increased when Gemcitabine for Injection, USP is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent. The frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in patients receiving Gemcitabine for Injection, USP in combination with another drug.

Pulmonary Toxicity and Respiratory Failure
Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of Gemcitabine for Injection, USP. Discontinue Gemcitabine for Injection, USP in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity.

Hemolytic Uremic Syndrome
Hemolytic Uremic Syndrome to include fatalities from renal failure or the requirement for dialysis can occur in patients treated with Gemcitabine for Injection, USP. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS. Assess renal function prior to initiation of Gemcitabine for Injection, USP and periodically during treatment. Consider the diagnosis of HUS in patients who develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN). Permanently discontinue Gemcitabine for Injection, USP in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy.

Hepatic Toxicity
Drug-induced liver injury, including liver failure and death, has been reported in patients receiving Gemcitabine for Injection, USP alone or in combination with other potentially hepatotoxic drugs. Administration of Gemcitabine for Injection, USP in patients with concurrent liver metastases or a pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency. Assess hepatic function prior to initiation of Gemcitabine for Injection, USP and periodically during treatment. Discontinue Gemcitabine for Injection, USP in patients that develop severe liver injury.

Embryofetal Toxicity
Gemcitabine for Injection, USP can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If this drug is used during pregnancy, or if a woman becomes pregnant while taking Gemcitabine for Injection, USP, the patient should be apprised of the potential hazard to a fetus.

Exacerbation of Radiation Therapy Toxicity
Gemcitabine for Injection, USP is not indicated for use in combination with radiation therapy.

Concurrent (given together or =7 days apart) - Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which Gemcitabine for Injection, USP was administered at a dose of 1000 mg/m2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation.

Non-concurrent (given >7 days apart) - Excessive toxicity has not been observed when Gemcitabine for Injection, USP is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive Gemcitabine for Injection, USP after prior radiation.

Capillary Leak Syndrome
Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving Gemcitabine for Injection, USP as a single agent or in combination with other chemotherapeutic agents. Discontinue Gemcitabine for Injection, USP if CLS develops during therapy.

ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in another section of the label

• Schedule-Dependent Toxicity
• Myelosuppression
• Pulmonary Toxicity and Respiratory Failure
• Hemolytic Uremic Syndrome
• Hepatic Toxicity
• Embryo-fetal Toxicity
• Exacerbation of Radiation Toxicity
• Capillary Leak Syndrome

Clinical Trials 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.

Single-Agent Use:
The data described below reflect exposure to Gemcitabine for Injection, USP as a single agent administered at doses between 800 mg/m2 to 1250 mg/m2 over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (=20%) adverse reactions of single-agent Gemcitabine for Injection, USP are nausea/vomiting, anemia, increased ALT, increased AST, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (=5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued Gemcitabine for Injection, USP due to adverse reactions. Adverse reactions resulting in discontinuation of Gemcitabine for Injection, USP in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of Gemcitabine for Injection, USP in less than 1% of the 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.

Table 5 presents the incidence of adverse reactions reported in 979 patients with various malignancies receiving single-agent Gemcitabine for Injection, USP across 5 clinical trials. Table 5 includes all clinical adverse reactions, reported in at least 10% of patients. A listing of clinically significant adverse reactions is provided following the table.

• Transfusion requirements - Red blood cell transfusions (19%); platelet transfusions (<1%)
• Fever - Fever occurred in the absence of clinical infection and frequently in combination with other flu-like symptoms.
• Pulmonary - Dyspnea unrelated to underlying disease and sometimes accompanied by bronchospasm.
• Edema - Edema (13%), peripheral edema (20%), and generalized edema (<1%); <1% of patients discontinued Gemcitabine for Injection, USP due to edema.
• Flu-like Symptoms - Characterized by fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia insomnia, rhinitis, sweating, and/or malaise (19%); <1% of patients discontinued Gemcitabine for Injection, USP due to flu-like symptoms
• Infection - Sepsis (<1%)
• Extravasation - Injection-site reactions (4%)
• Allergic - Bronchospasm (<2%); anaphylactoid reactions.

Non-Small Cell Lung Cancer:
Table 6 presents the incidence of selected adverse reactions, occurring in =10% of Gemcitabine for Injection, USP-treated patients and at a higher incidence in the Gemcitabine for Injection, USP plus cisplatin arm, reported in a randomized trial of Gemcitabine for Injection, USP plus cisplatin (n=262) administered in 28-day cycles as compared to cisplatin alone (n=260) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC).

Patients randomized to Gemcitabine for Injection, USP plus cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving Gemcitabine for Injection, USP plus cisplatin arm compared to those receiving cisplatin alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the Gemcitabine for Injection, USP plus cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm.

Table 7 presents the incidence of selected adverse reactions, occurring in =10% of Gemcitabine for Injection, USP-treated patients and at a higher incidence in the Gemcitabine for Injection, USP plus cisplatin arm, reported in a randomized trial of Gemcitabine for Injection, USP plus cisplatin (n=69) administered in 21-day cycles as compared to etoposide plus cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC). A listing of clinically significant adverse reactions is provided following the table.

Patients in the Gemcitabine for Injection, USP cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the (GC) arm and 68% in the (EC) arm. The incidence of hospitalizations for treatment-related adverse events was 22% (GC) and 27% in the (EC) arm. The proportion of discontinuation of treatment for treatment-related adverse reactions was higher for patients in the (GC) arm (14% versus 8%). The proportion of patients hospitalized for febrile neutropenia was lower in the (GC) arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the Gemcitabine for Injection, USP/cisplatin arm.

• Flu-like syndrome: 3% in the Gemcitabine for Injection, USP/cisplatin arm versus none in the etoposide/cisplatin arm.
• Edema: 12% in the Gemcitabine for Injection, USP/cisplatin arm versus 2% in the etoposide/cisplatin arm.

Breast Cancer
Table 8 presents the incidence of selected adverse reactions, occurring in =10% of Gemcitabine for Injection, USP-treated patients and at a higher incidence in the Gemcitabine for Injection, USP plus paclitaxel arm, reported in a randomized trial of Gemcitabine for Injection, USP plus paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated.

The requirement for dose reduction of paclitaxel were higher for patients in the Gemcitabine for Injection, USP/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for treatment-related adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.

The following clinically relevant, Grade 3 or 4 adverse reactions occurred with a higher incidence in the Gemcitabine for Injection, USP plus paclitaxel arm compared with the paclitaxel arm: febrile neutropenia (5.0% versus 1.2%) and dyspnea (1.9% versus 0).

Ovarian Cancer
Table 9 presents the incidence of selected adverse reactions, occurring in =10% of gemcitabine-treated patients and at a higher incidence in the Gemcitabine for Injection, USP plus carboplatin arm, reported in a randomized trial of Gemcitabine for Injection, USP plus carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy.

The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0), and discontinuing treatment for treatment-related adverse reactions (10.9% versus 9.8%), were similar between arms. Dose adjustment for Gemcitabine for Injection, USP occurred in 10.4% of patients and Gemcitabine for Injection, USP dose was omitted in 13.7% of patients in the Gemcitabine for Injection, USP/carboplatin arm.

Hematopoietic growth factors were administered more frequently in the Gemcitabine for Injection, USP-containing arm: granulocyte growth factors (23.6% and 10.1%) and erythropoietic agents (7.3% and 3.9%).

The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the Gemcitabine for Injection, USP plus carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of Gemcitabine for 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.

• Cardiovascular - Congestive heart failure, myocardial infarction, Arrhythmias, supraventricular arrhythmias.
• Vascular Disorders - Peripheral vasculitis, gangrene, and capillary leak syndrome
• Skin - Cellulitis, severe skin reactions, including desquamation and bullous skin eruptions
• Hepatic - Hepatic failure, hepatic veno-occlusive disease
• Pulmonary - Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS)

DRUG INTERACTIONS

No drug interaction studies have been conducted.

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category D. [see Warnings and Precautions]

Risk Summary
Gemcitabine for Injection, USP can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, Gemcitabine for Injection, USP is expected to result in adverse reproductive effects. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If Gemcitabine for Injection, USP is used during pregnancy, or if the patient becomes pregnant while taking Gemcitabine for Injection, USP, the patient should be apprised of the potential hazard to a fetus.

Animal Data
Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (approximately 0.005 times the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 0.002 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays.

Nursing Mothers
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 Gemcitabine for Injection, USP, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use
The safety and effectiveness of Gemcitabine for Injection, USP have not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. The safety and activity of Gemcitabine for Injection, USP were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m2/min administered over 360 minutes three times weekly followed by a one-week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial.

Geriatric Use
In clinical studies of Gemcitabine for Injection, USP, enrolling 979 patients with various cancers who received Gemcitabine for Injection, USP as a single agent, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the exception of a higher rate of Grade 3-4 thrombocytopenia in older patients as compared to younger patients. In a randomized trial in women with ovarian cancer, 175 women received Gemcitabine for Injection, USP plus carboplatin, of which 29% were age 65 years or older. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older.

Gemcitabine for Injection, USP clearance is affected by age, however there are no recommended dose adjustments based on patients' age.

Renal Impairment
No clinical studies have been conducted with gemcitabine in patients with decreased renal function.

Hepatic Impairment
No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function.

Gender
Gemcitabine for Injection, USP clearance is affected by gender. In single-agent studies of Gemcitabine for Injection, USP, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia.

OVERDOSAGE

Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study.

DESCRIPTION

Gemcitabine for Injection, USP is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine hydrochloride, USP is 2'-deoxy-2',2'-difluorocytidine monohydrochloride (ß-isomer).

The structural formula is as follows:

The molecular formula for gemcitabine hydrochloride, USP is C9H11F2N3O4 • HCl. It has a molecular weight of 299.66.

Gemcitabine hydrochloride, USP is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.

Gemcitabine for Injection, USP is supplied in a sterile form for intravenous use only. Vials of Gemcitabine for Injection, USP contain either 200 mg or 1 g of gemcitabine hydrochloride, USP (expressed as free base) formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. Sodium hydroxide may have been added for pH adjustment.

CLINICAL PHARMACOLOGY

Mechanism of Action
Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands, which eventually results in the initiation of apoptotic cell death.

Pharmacokinetics

Absorption and Distribution
The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokinetic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total Gemcitabine for Injection, USP dose varied from 500 to 3600 mg/m2.

The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2.

Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is negligible.

Metabolism
Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m2/30 minute infusion of radiolabeled drug. Within one week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2'-deoxy-2',2'-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma.

The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours.

Elimination
Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 10 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender.

Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions.

Drug Interactions
When Gemcitabine for Injection, USP (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. Analysis of data from metastatic breast cancer patients shows that, on average, Gemcitabine for Injection, USP has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine. Data from NSCLC patients demonstrate that Gemcitabine for Injection, USP and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies to evaluate the carcinogenic potential of Gemcitabine for Injection, USP have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the human dose on a mg/m2 basis).

CLINICAL STUDIES

Ovarian Cancer
The safety and efficacy of Gemcitabine for Injection, USP was studied in a randomized trial of 356 women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either Gemcitabine for Injection, USP 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemcitabine for Injection, USP infusion on Day 1 of each cycle (n=178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n=178). The primary efficacy outcome measure was progression free survival (PFS).

Patient characteristics are shown in Table 11. The addition of Gemcitabine for Injection, USP to carboplatin resulted in statistically significant improvements in PFS and overall response rate as shown in Table 12 and Figure 1. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received Gemcitabine for Injection, USP for treatment of disease progression. There was no significant difference in overall survival between the treatment arms.

Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabine for Injection, USP plus Carboplatin versus Carboplatin in Ovarian Cancer (N=356)

Breast Cancer
The safety and efficacy of Gemcitabine for Injection, USP were evaluated in a multi-national, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer in women who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive Gemcitabine for Injection, USP 1250 mg/m2 on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m2 administered prior to Gemcitabine for Injection, USP on Day 1 of each cycle (n=267) or to receive paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle (n=262). The primary efficacy outcome measure was time to documented disease progression.

A total of 529 patients were enrolled; 267 were randomized to Gemcitabine for Injection, USP and paclitaxel and 262 to paclitaxel alone. Demographic and baseline characteristics were similar between treatment arms (see Table 13). Efficacy results are presented in Table 13 and Figure 2. The addition of Gemcitabine for Injection, USP to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant difference in overall survival.

Figure 2: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemcitabine for Injection, USP plus Paclitaxel versus Paclitaxel Breast Cancer Study (N=529)

Non-Small Cell Lung Cancer (NSCLC)
The safety and efficacy of Gemcitabine for Injection, USP was evaluated in two randomized, multicenter trials.

28-Day Schedule
A multinational, randomized trial compared Gemcitabine for Injection, USP plus cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive Gemcitabine for Injection, USP 1000 mg/m2 on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each cycle or to receive cisplatin 100 mg/m2 on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall survival. A total of 522 patients were enrolled at clinical centers in Europe, the US, and Canada. Patient demographics and baseline characteristics (shown in Table 14) were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the Gemcitabine for Injection, USP plus cisplatin arm having adenocarcinoma. Efficacy results are presented in Table 14 and Figure 3 for overall survival.

21-Day Schedule
A randomized (1:1), multicenter trial was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were randomized to receive Gemcitabine for Injection, USP 1250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to receive etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21 -day cycle.

There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided). The median survival was 8.7 months for the Gemcitabine for Injection, USP plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the Gemcitabine for Injection, USP plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the Gemcitabine for Injection, USP plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher's Exact p=0.01, two-sided).

Figure 3: Kaplan-Meier Survival Curve in Gemcitabine for Injection, USP plus Cisplatin versus Cisplatin in Patients with NSCLC Study (N=522)

Pancreatic Cancer
The safety and efficacy of Gemcitabine for Injection, USP was evaluated in two trials, a randomized, single-blind, two-arm, active-controlled trial conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The first trial randomized patients to receive Gemcitabine for Injection, USP 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or to 5-fluorouracil (5-FU) 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In the second trial, all patients received Gemcitabine for Injection, USP 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles.

The primary efficacy outcome measure in both trials was "clinical benefit response". A patient was considered to have had a clinical benefit response if either occurred:

• The patient achieved a =50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy.
  
  OR
• The patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain (=7% increase maintained for =4 weeks) not due to fluid accumulation.

The randomized trial enrolled 126 patients across 17 sites in the US and Canada. The demographic and entry characteristics were similar between the arms (Table 15). The efficacy outcome results are shown in Table 15 and for overall survival in Figure 4. Patients treated with Gemcitabine for Injection, USP had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive 5-FU. No confirmed objective tumor responses were observed in either treatment arm.

Figure 4: Kaplan-Meier Survival Curve

HOW SUPPLIED/STORAGE AND HANDLING

How Supplied
Gemcitabine for Injection, USP is supplied as follows:

Gemcitabine for Injection, USP is a white, lyophilized powder.

Sterile, Nonpyrogenic, Preservative-free.
The container closure is not made with natural rubber latex.

Storage and Handling
Unopened vials of Gemcitabine for Injection, USP are stable until the expiration date indicated on the package when stored at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.]

PATIENT COUNSELING INFORMATION

• Advise patients of the risks of low blood cell counts and the potential need for blood transfusions and increased susceptibility to infections. Instruct patients to immediately contact their healthcare provider for development of signs or symptoms of infection, fever, prolonged or unexpected bleeding, bruising, or shortness of breath
• Advise patients of the risks of pulmonary toxicity including respiratory failure and death. Instruct patients to immediately contact their healthcare provider for development of shortness of breath, wheezing, or cough
• Advise patients of the risks of hemolytic-uremic syndrome and associated renal failure. Instruct patients to immediately contact their healthcare provider for changes in the color or volume of urine output or for increased bruising or bleeding
• Advise patients of the risks of hepatic toxicity including liver failure and death. Instruct patients to immediately contact their healthcare provider for signs of jaundice or for pain/tenderness in the right upper abdominal quadrant