post-title portfolio-title Gemcitabine Powder for Solution for Infusion IP 200mg Taj Pharma 2020-02-24 12:10:11 no no

Gemcitabine Powder for Solution for Infusion IP 200mg Taj Pharma

Overview

INTRODUCTION

Gemcitabine 200mg Injection is used in the treatment of non-small cell lung cancer, breast cancer, pancreatic cancer, urinary bladder cancer, and ovarian cancer.

Gemcitabine 200mg Injection is given as an injection by a qualified medical professional. Your doctor will decide what dose is necessary and how often you need to take it. This will depend on what you are being treated for and may change from time to time. You should take it exactly as your doctor has advised. Taking it in the wrong way or taking too much can cause very serious side effects. It may take several weeks or months for you to see or feel the benefits but do not stop taking it unless your doctor tells you to.

The most common side effects of this medicine include nausea, vomiting, loss of appetite, hair loss and low blood platelets. This medicine may reduce the number of blood cells (decrease red blood and white blood cells) in your blood, thereby, increasing the susceptibility to infections. Regular blood tests are required to check your blood cells along with heart, liver, and blood uric acid levels.

Before taking it, tell your doctor if you have heart disease, liver, or kidney problems or are taking any medicines to treat infections. Many other medicines can affect, or be affected by, this medicine so let your doctor know all medications you are using. This medicine is not recommended during pregnancy or while breastfeeding. The use of effective contraception by both males and females during treatment is important to avoid pregnancy.

USES OF GEMCITABINE INJECTION

  • Non-small cell lung cancer
  • Breast cancer
  • Pancreatic cancer
  • Urinary bladder cancer
  • Ovarian cancer

SIDE EFFECTS OF GEMCITABINE INJECTION

Common

  • Nausea
  • Vomiting
  • Loss of appetite
  • Hair loss
  • Low blood platelets
  • Allergic reaction
  • Breathlessness
  • Decreased white blood cell count
  • Increased liver enzymes
  • Anemia (low number of red blood cells)
  • Flu-like symptoms
  • Blood in urine
  • Skin rash
  • Protein in urine

HOW TO USE GEMCITABINE INJECTION

Your doctor or nurse will give you this medicine. Kindly do not self administer.

HOW GEMCITABINE INJECTION WORKS

Gemcitabine 200mg Injection interferes with the growth of DNA and RNA of the cancer cells by substituting their building blocks. It prevents the cancer cells from growing and multiplying.

SAFETY ADVICE

warningsAlcohol

UNSAFE

Gemcitabine 200mg Injection may cause excessive drowsiness with alcohol.

warningsPregnancy

CONSULT YOUR DOCTOR

Gemcitabine 200mg Injection is unsafe to use during pregnancy as there is definite evidence of risk to the developing baby. However, the doctor may rarely prescribe it in some life-threatening situations if the benefits are more than the potential risks. Please consult your doctor.

warningsBreastfeeding

UNSAFE

Gemcitabine 200mg Injection is unsafe to use during breastfeeding. Data suggests that the drug may cause toxicity to the baby.

warningsDriving

UNSAFE

Gemcitabine 200mg Injection may decrease alertness, affect your vision or make you feel sleepy and dizzy. Do not drive if these symptoms occur.

warningsKidney

CONSULT YOUR DOCTOR

There is limited information available on the use of Gemcitabine 200mg Injection in patients with kidney disease. Please consult your doctor.
Kidney function tests are advised before taking this medicine and regular monitoring is also recommended after the treatment.

warningsLiver

CONSULT YOUR DOCTOR

There is limited information available on the use of Gemcitabine 200mg Injection in patients with liver disease. Please consult your doctor.

Gemcitabine Powder for Solution for Infusion IP 200mg Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT
a) Gemcitabine Powder for Solution for Infusion IP 200mg Taj Pharma

b) Gemcitabine Powder for Solution for Infusion IP 1g Taj Pharma

2.QUALITATIVE AND QUANTITATIVE COMPOSITION??????????????????????????????

a) Each sterile lyophilized vial contains
Gemcitabine Hydrochloride IP
Equivalent to Gemcitabine 200mg
Mannitol??????????????????? 200mg
Sodium Acetate????????? 5mg
Sodium Hydroxide?? q.s.
Hydroxide Acid??????? q.s.

b) Each sterile lyophilized vial contains
Gemcitabine Hydrochloride IP
Equivalent to Gemcitabine 1000mg
Mannitol??????????? 1000mg
Sodium Acetate?? 5mg
Sodium Hydroxide?? q.s.
Hydroxide Acid????? q.s.

For a full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM????

Powder for solution for infusion (powder for infusion)

White to off-white plug or powder.

4.CLINICAL PARTICULARS

4.1 Therapeutic indications

Bladder Cancer:

Locally advanced or metastatic bladder cancer, in combination with cisplatin.

Pancreatic Cancer:

Locally advanced or metastatic adenocarcinoma of the pancreas.

Non-Small Cell Lung Cancer:

First-line treatment of patients with locally advanced or metastatic non-small cell lung cancer, in combination with cisplatin. Gemcitabine monotherapy can be considered in elderly patients or those with performance status 2.

Ovarian Cancer:

Locally advanced or metastatic epithelial ovarian carcinoma, in combination with carboplatin, in patients with relapsed disease following a recurrence-free interval of at least 6 months after platinum-based, first line therapy.

Breast Cancer:

Unresectable, locally recurrent or metastatic breast cancer, in combination with paclitaxel, in patients experiencing a relapse after adjuvant/neoadjuvant chemotherapy. The preceding chemotherapy should have included an anthracycline, unless clinically contraindicated.

4.2 Posology and method of administration

For intravenous infusion, following reconstitution. Upon reconstitution a colourless or slightly yellow solution is produced.

Gemcitabine should only be prescribed by a physician qualified in the use of anti-cancer chemotherapy.

Bladder cancer (combination therapy):

Adults:?The recommended dose for gemcitabine is 1000 mg/m2, given as a 30 minute infusion. The dose should be given on days 1, 8, and 15 of each 28 day cycle in combination with cisplatin. Cisplatin is given at a recommended dose of 70 mg/m2?on day 1 following gemcitabine, or day 2 of each 28 day cycle. This four week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.

Pancreatic Cancer:

Adults:?The recommended dose of gemcitabine is 1000 mg/m2, given by 30 minute intravenous infusion. This should be repeated once weekly for up to 7 weeks, followed by a one week rest period. Subsequent cycles should consist of gemcitabine infusions once weekly for 3 consecutive weeks out of every four weeks. Dosage reduction with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.

Non-small cell lung cancer (monotherapy):

Adults:?The recommended dose of gemcitabine is 1000 mg/m2, given by 30 minute intravenous infusion. This should be repeated once weekly for three weeks, followed by a one week rest period. This four-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.

Non-small cell lung cancer (combination therapy):

Adults:?The recommended dose of gemcitabine is 1250 mg/m2, given by 30 minute intravenous infusion, on days 1 and 8 of each 21 day cycle. Dosage reduction with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.

Cisplatin has been used at doses between 75-100 mg/m2?once every 3 weeks.

Ovarian cancer (combination therapy):

The recommended dose of gemcitabine, when used in combination with carboplatin, is 1000 mg/m2, given by 30 minute intravenous infusion on days 1 and 8 of each 21 day cycle. After gemcitabine, carboplatin will be given on day 1, consistent with a target Area Under Curve (AUC) of 4.0mg/ml/min. Dosage reduction with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.

Breast cancer (combination therapy):

Adults:?It is recommended that gemcitabine is used together with paclitaxel according to the following procedure:

Paclitaxel (175 mg/m2) is intravenously infused over 3 hours on day 1, followed by gemcitabine (1250 mg/m2) intravenously infused for 30 minutes on days 1 and 8 of each 21 day treatment cycle. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient. The absolute granulocyte count should be at least 1.5 x 109/l before treatment with the gemcitabine + paclitaxel combination.

Monitoring for toxicity and dose modification due to toxicity

Dosage adjustment due to non haematological toxicity:

Periodic physical examination and checks of renal and hepatic function should be made to detect non-haematological toxicity. Dosage reduction with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient. In general, for severe (Grade 3 or 4) non-haematological toxicity, except nausea/vomiting, therapy with gemcitabine should be withheld or decreased depending on the judgement of the treating physician. Doses should be withheld until toxicity has been resolved.

For cisplatin, carboplatin, and paclitaxel dosage adjustment in combination therapy, please refer to the corresponding Summary of Product Characteristics.

Dosage adjustment in the presence of haematological toxicity:

Initiation of a cycle

For all indications, patients must be monitored before each dose for platelet and granulocyte counts. Patients should have an absolute granulocyte count of at least 1,500 (x106/l) and a platelet count of 100,000 (x106/l) prior to the administration of a cycle.

Within a cycle

Dose modifications of gemcitabine within a cycle should be performed according to the following tables:

 

Dose modification of gemcitabine within a cycle for bladder cancer, pancreatic cancer, and NSCLC, given in monotherapy or in combination with cisplatin
Absolute Granulocyte Count

(x 109/l)

Platelet Count

(x 109/l)

% of

Total Dose

> 1and>100100
0.5-1or50-10075
< 0.5or<50Withhold*

*Withheld treatment will not be reinstated within a cycle before the absolute granulocyte count reaches at least 0.5(x 109/l) and the platelet count reaches 50 (x 109/l).

Dose modification of gemcitabine within a cycle for ovarian cancer, given in combination with carboplatin
Absolute Granulocyte Count

(x 109/l)

Platelet Count

(x 109/l)

% of

Total Dose

>1.5and>100100
1-1.5or75-10050
<1or<75Withhold*

*Withheld treatment will not be reinstated within a cycle. Treatment will start on day 1 of the next cycle once the absolute granulocyte count reaches at least 1.5(x 109/l) and the platelet count reaches 100 (x 109/l)

Dose modification of gemcitabine within a cycle for breast cancer, given in combination with paclitaxel
Absolute Granulocyte Count

(x 109/l)

Platelet Count

(x 109/l)

% of

Total Dose

?1.2and>75100
1-<1.2or50-7575
0.7-<1and?5050
<0.7or<50Withhold*

*Withheld treatment will not be reinstated within a cycle. Treatment will start on day 1 of the next cycle once the absolute granulocyte count reaches at least 1.5 (x 109/l) and the platelet count reaches 100 (x 109/l).

Dose adjustment due to haematological toxicity in subsequent cycles, for all indications

The gemcitabine dose should be reduced to 75% of the original cycle initiation dose, in the case of the following haematological toxicities:

  • Absolute granulocyte count < 0.5 x 109/l for more than 5 days
  • Absolute granulocyte count < 0.1 x 109/l for more than 3 days
  • Febrile neutropaenia
  • Platelets <25 x 109/l
  • Cycle delay of more than one week due to toxicity

Method of administration

Gemcitabine is tolerated well during infusion and may be administered ambulant. If extravasation occurs, generally the infusion must be stopped immediately and started again in another blood vessel. The patient should be monitored carefully after the administration.

For instructions on reconstitution, see section 6.6

Special Populations

Patients with hepatic or renal impairment:

Gemcitabine should be used with caution in patients with hepatic or renal impairment as there is insufficient information from clinical studies to allow for clear dose recommendations for these patient populations (see sections 4.4 and 5.2).

Elderly population (>65 years):

Gemcitabine has been well tolerated in patients over the age of 65. There is no evidence to suggest that dose adjustments, other than those already recommended for all patients, are necessary in the elderly (see section 5.2).

Paediatric population (<18 years):

Gemcitabine is not recommended for use in children under 18 years of age due to insufficient data on safety and efficacy.

4.3 Contraindications

Hypersensitivity to gemcitabine or to any of the excipients

Breast-feeding (see section 4.6)

4.4 Special warnings and precautions for use

Hypertension, hypokalaemia, fluid retention and cardiac failure due to mineralocorticoid excess

Abiraterone Acetate may cause hypertension, hypokalaemia and fluid retention (see section 4.8) as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see section 5.1). Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in incidence and severity of these adverse reactions. Caution is required in treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalaemia (e.g., those on cardiac glycosides), or fluid retention (e.g., those with heart failure, severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those with severe renal impairment).

Abiraterone Acetate should be used with caution in patients with a history of cardiovascular disease. The Phase 3 studies conducted with Abiraterone Acetate excluded patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association Class (NYHA) III or IV heart failure (study 301) or Class II to IV heart failure (studies 3011 and 302) or cardiac ejection fraction measurement of < 50%. In studies 3011 and 302, patients with atrial fibrillation, or other cardiac arrhythmia requiring medical therapy were excluded. Safety in patients with left ventricular ejection fraction (LVEF) < 50% or NYHA Class III or IV heart failure (in study 301) or NYHA Class II to IV heart failure (in studies 3011 and 302) was not established (see sections 4.8 and 5.1).

Before treating patients with a significant risk for congestive heart failure (e.g.a history of cardiac failure, uncontrolled hypertension, or cardiac events such as ischaemic heart disease), consider obtaining an assessment of cardiac function (e.g. echocardiogram). Before treatment with Abiraterone Acetate, cardiac failure should be treated and cardiac function optimised. Hypertension, hypokalaemia and fluid retention should be corrected and controlled. During treatment, blood pressure, serum potassium, fluid retention (weight gain, peripheral oedema), and other signs and symptoms of congestive heart failure should be monitored every 2 weeks for 3 months, then monthly thereafter and abnormalities corrected. QT prolongation has been observed in patients experiencing hypokalaemia in association with Abiraterone Acetate treatment. Assess cardiac function as clinically indicated, institute appropriate management and consider discontinuation of this treatment if there is a clinically significant decrease in cardiac function (see section 4.2).

Hepatotoxicity and hepatic impairment

Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurred in controlled clinical studies (see section 4.8). Serum transaminase levels should be measured prior to starting treatment, every two weeks for the first three months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should be measured immediately. If at any time the ALT or AST rises above 5 times the ULN, treatment should be interrupted immediately and liver function closely monitored. Re-treatment may take place only after return of liver function tests to the patient’s baseline and at a reduced dose level (see section 4.2).

If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy, treatment should be discontinued and patients should not be re-treated.

Patients with active or symptomatic viral hepatitis were excluded from clinical trials; thus, there are no data to support the use of Abiraterone Acetate in this population.

There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The use of Abiraterone Acetate should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see sections 4.2 and 5.2). Abiraterone Acetate should not be used in patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2).

There have been rare post-marketing reports of acute liver failure and hepatitis fulminant, some with fatal outcome (see section 4.8).

Corticosteroid withdrawal and coverage of stress situations

Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are withdrawn from prednisone or prednisolone. If Abiraterone Acetate is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see information above).

In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose of corticosteroids may be indicated before, during and after the stressful situation.

Bone density

Decreased bone density may occur in men with metastatic advanced prostate cancer. The use of Abiraterone Acetate in combination with a glucocorticoid could increase this effect.

Prior use of ketoconazole

Lower rates of response might be expected in patients previously treated with ketoconazole for prostate cancer.

Hyperglycaemia

The use of glucocorticoids could increase hyperglycaemia, therefore blood sugar should be measured frequently in patients with diabetes.

Use with chemotherapy

The safety and efficacy of concomitant use of Abiraterone Acetate with cytotoxic chemotherapy has not been established (see section 5.1).

Intolerance to excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicinal product also contains more than 1.18 mmol (or 27 mg) sodium per dose of two tablets. To be taken into consideration by patients on a controlled sodium diet.

Potential risks

Anaemia and sexual dysfunction may occur in men with metastatic prostate cancer including those undergoing treatment with Abiraterone Acetate.

Skeletal muscle effects

Cases of myopathy have been reported in patients treated with Abiraterone Acetate. Some patients had rhabdomyolysis with renal failure. Most cases developed within the first month of treatment and recovered after Abiraterone Acetate withdrawal. Caution is recommended in patients concomitantly treated with medicinal products known to be associated with myopathy/rhabdomyolysis.

Interactions with other medicinal products

Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeutic alternative, due to risk of decreased exposure to abiraterone (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Effect of food on abiraterone acetate

Administration with food significantly increases the absorption of abiraterone acetate. The efficacy and safety when given with food have not been established therefore this medicinal product must not be taken with food (see sections 4.2 and 5.2).

Interactions with other medicinal products

Potential for other medicinal products to affect abiraterone exposures

In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer rifampicin, 600 mg daily for 6 days followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC??of abiraterone was decreased by 55%.

Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John’s wort [Hypericum perforatum]) during treatment are to be avoided, unless there is no therapeutic alternative.

In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

Potential to affect exposures to other medicinal products

Abiraterone is an inhibitor of the hepatic drug-metabolising enzymes CYP2D6 and CYP2C8.

In a study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased approximately 2.9 fold. The AUC24?for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%.

Caution is advised when administering with medicinal products activated by or metabolised by CYP2D6, particularly with medicinal products that have a narrow therapeutic index. Dose reduction of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6 should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol (the latter three medicinal products requiring CYP2D6 to form their active analgesic metabolites).

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% and the AUCs for M-III and M-IV, the active metabolites of pioglitazone, each decreased by 10% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Although these results indicate that no clinically meaningful increases in exposure are expected when Abiraterone Acetate is combined with medicinal products that are predominantly eliminated by CYP2C8, patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly.

In vitro, the major metabolites abiraterone sulphate and N-oxide abiraterone sulphate were shown to inhibit the hepatic uptake transporter OATP1B1 and as a consequence it may increase the concentrations of medicinal products eliminated by OATP1B1. There are no clinical data available to confirm transporter based interaction.

?

Use with products known to prolong QT interval

Since androgen deprivation treatment may prolong the QT interval, caution is advised when administering Abiraterone Acetate with medicinal products known to prolong the QT interval or medicinal products able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc.

Use with Spironolactone

Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels. Use with Abiraterone Acetate is not recommended (see section 5.1).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

There are no human data on the use of Abiraterone Acetate in pregnancy and this medicinal product is not for use in women of childbearing potential.

Contraception in males and females

It is not known whether abiraterone or its metabolites are present in semen. A condom is required if the patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sex with a woman of childbearing potential, a condom is required along with another effective contraceptive method. Studies in animals have shown reproductive toxicity (see section 5.3).

Pregnancy

Abiraterone Acetate is not for use in women and is contraindicated in women who are or may potentially be pregnant (see section 4.3 and 5.3).

Breast-feeding

Abiraterone Acetate is not for use in women.

Fertility

Abiraterone affected fertility in male and female rats, but these effects were fully reversible (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, gemcitabine has been reported to cause mild to moderate somnolence, especially in combination with alcohol consumption. Patients should be cautioned against driving or operating machinery until it is established that they do not become somnolent.

4.8 Undesirable effects

The most commonly reported adverse reactions associated with gemcitabine treatment include: nausea, with or without vomiting, and raised liver transaminases ( (AST/ ALT) and alkaline phosphatase, reported in approximately 60% of patients; proteinuria and haematuria reported in approximately 50% of patients; dyspnoea reported in 10-40% of patients (highest incidence in lung cancer patients); allergic skin rashes occurring in approximately 25% of patients, and are associated with itching in 10% of patients.

The frequency and severity of the adverse reactions are affected by the dose, infusion rate, and intervals between doses (see section 4.4). Dose-limiting adverse reactions are reductions in thrombocyte, leucocyte, and granulocyte counts (see section 4.2).

Clinical trial data

Frequencies are defined as: Very common (?1/10); common (?1/100 to <1/10); uncommon (?1/1,000 to <1/100); rare (?1/10,000 to <1/1,000); very rare (<1/10,000).

System Organ ClassFrequency Grouping
Blood and lymphatic system disordersVery common:

? Leucopenia (Neutropaenia grade 3 =19.3% ; grade 4 =6%)

? Thrombocytopaenia

? Anaemia

Bone marrow suppression is usually mild to moderate and mostly affects the granulocyte count (see section 4.2)

Common:

? Febrile neutropenia

Very rare:

? Thrombocytosis

Immune system disordersVery Rare:

? Anaphylactoid reaction

Metabolism and nutrition disordersCommon:

? Anorexia

Nervous system disordersCommon:

??Headache

??Insomnia

??Somnolence

Uncommon

Cerebrovascular accident

Cardiac disordersUncommon:

? Arrhythmias, predominantly supraventricular in nature

? Heart failure

Rare:

? Myocardial infarct

Vascular disordersRare:

? Clinical signs of peripheral vasculitis and gangrene

? Hypotension

Respiratory, thoracic and mediastinal disordersVery common:

? Dyspnoea -usually mild and passes rapidly without treatment

Common:

? Cough

? Rhinitis

Uncommon:

? Interstitial pneumonitis (see section 4.4)

? Bronchospasm ? usually mild and transient but may require parenteral treatment

Rare:

? Pulmonary oedema

? Adult respiratory distress syndrome (see section 4.4)

Gastrointestinal disordersVery common:

? Vomiting

? Nausea

Common:

? Diarrhoea

? Stomatitis & ulceration of the mouth

? Constipation

Very rare:

? Ischaemic colitis

Hepatobiliary disordersVery common:

? Elevation of liver transaminases (AST and ALT) and alkaline phosphatase

Common:

? Increased bilirubin

Uncommon:

? Serious hepatotoxicity, including liver failure and death

Rare:

? Increased gamma glutamyl transferase (GGT)

Skin and subcutaneous tissue disordersVery common:

? Allergic skin rash frequently associated with pruritus

? Alopecia

Common:

? Itching

? Sweating

Rare:

? Severe skin reactions, including desquamation and bullous skin eruptions

? Ulceration

? Vesicle and sore formation

? Scaling

Very rare:

? Toxic epidermal necrolysis

? Stevens-Johnson Syndrome

Musculoskeletal and connective tissue disordersCommon:

??Back pain

??Myalgia

Renal and urinary disordersVery common:

? Haematuria

? Mild proteinurea

Uncommon:

? Renal failure (see section 4.4)

? Haemolytic uraemic syndrome (see section 4.4)

General disorders and administration site conditionsVery common:

? Influenza-like symptoms -the most common symptoms are fever, headache, chills, myalgia, asthenia, and anorexia. Cough, rhinitis, malaise, perspiration and sleeping difficulties have also been reported.

? Oedema/peripheral oedema ? including facial oedema. Oedema is usually reversible after stopping treatment

Common:

? Fever

? Asthenia

? Chills

Rare:

? Injection site reactions -mainly mild in nature

Injury, poisoning, and procedural complicationsRare:

? Radiation toxicity (see section 4.5)

? Radiation recall

Combination use in breast cancer
The frequency of grade 3 and 4 haematological toxicities, particularly neutropaenia, increases when gemcitabine is used in combination with paclitaxel. However, the increase in these adverse reactions is not associated with an increased incidence of infections or haemorrhagic events. Fatigue and febrile neutropaenia occur more frequently when gemcitabine is used in combination with paclitaxel. Fatigue, which is not associated with anaemia, usually resolves after the first cycle.

Grade 3 and 4 Adverse Events. Paclitaxel versus gemcitabine plus paclitaxel:

Number (%) of Patients
Paclitaxel Arm

(n= 259)

Gemcitabine plus

Paclitaxel Arm (n= 262)

Grade 3Grade 4Grade 3Grade 4
Laboratory
Anaemia5(1.9)1 (0.4)15 (5.7)3 (1.1)
Thrombocytopaenia0014 (5.3)1 (0.4)
Neutropaenia11 (4.2)17 (6.6)*82 (31.3)45 (17.2)*
Non-laboratory
Febrile neutropenia3 (1.2)012 (4.6)1 (0.4)
Fatigue3 (1.2)1 (0.4)15 (5.7)2 (0.8)
Diarrhoea5 (1.9)08(3.1)0
Motor neuropathy2 (0.8)06 (2.3)1 (0.4)
Sensory neuropathy9 (3.5)014 (5.3)1 (0.4)

* Grade 4 neutropenia lasting for more than 7 days occurred in 12.6% of patients in the combination arm and 5.0% of patients in the paclitaxel arm.

Combination use in bladder cancer

Grade 3 and 4 Adverse Events. MVAC versus gemcitabine plus cisplatin:

Number (%) of Patients
MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) Arm (n= 196)Gemcitabine plus cisplatin Arm (n= 200)
Grade 3Grade 4Grade 3Grade 4
Laboratory
Anaemia30 (16)4 (2)47 (24)7 (4)
Thrombocytopaenia15 (8)25 (13)57 (29)57 (29)
Non-laboratory
Nausea and vomiting37 (19)3 (2)44 (22)0 (0)
Diarrhoea15 (8)1 (1)6 (3)0 (0)
Infection19 (10)10 (5)4 (2)1 (1)
Stomatitis34 (18)8 (4)2 (1)0 (0)

?

Combination use in ovarian cancer

Grade 3 and 4 Adverse Events. Carboplatin versus gemcitabine plus carboplatin:

Number (%) of Patients
Carboplatin Arm (n= 174)Gemcitabine plus carboplatin Arm (n= 175)
Grade 3Grade 4Grade 3Grade 4
Laboratory
Anaemia10 (5.7)4 (2.3)39 (22.3)9 (5.1)
Neutropaenia19 (10.9)2 (1.1)73 (41.7)50 (28.6)
Thrombocytopaenia18 (10.3)2 (1.1)53 (30.3)8 (4.6)
Leucopaenia11 (6.3)1 (0.6)84 (48.0)9 (5.1)
Non-laboratory
Haemorrhage0 (0.0)0 (0.0)3 (1.8)(0.0)
Febrile neutropaenia0 (0.0)0 (0.0)2 (1.1)(0.0)
Infection without neutropaenia0 (0)0 (0.0)(0.0)1 (0.6)

Sensory neuropathy was also more frequent in the combination arm than with single agent carboplatin.

4.9 Overdose

There is no known antidote for overdose of gemcitabine. Single doses of up to 5.7 g/m2?have been administered as intravenous infusions over 30 minutes every two weeks, with clinically acceptable toxicity. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy as necessary.

5.PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: pyrimidine analogues

Cytotoxic Activity in Cell Culture Models:

Gemcitabine exhibits significant cytotoxicity activity against a variety of cultured murine and human tumour cells. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells through the G1/S-phase boundary.?In vitro?the cytotoxic action of gemcitabine is both concentration and time dependent.

Antitumour Activity in Preclinical Models:

In animal tumour models, the antitumour activity of gemcitabine is schedule dependent. When gemcitabine is administered daily, high animal mortality but minimal antitumoural activity is seen. If, however, gemcitabine is given every third or fourth day, it can be administered in non-lethal doses with substantial antitumoural activity against a broad spectrum of mouse tumours.

Cellular Metabolism and Mechanisms of Action:

Gemcitabine (dFdC), which is a pyrimidine antimetabolite, is metabolised intracellularly by nucleoside kinase to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic action of gemcitabine is due to inhibition of DNA synthesis by two actions of dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase, which is uniquely responsible for catalysing the reactions that generate the deoxynucleoside triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme by dFdCDP causes a reduction in the concentrations of deoxynucleosides in general, and especially in that of dCTP. Second, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation).

Likewise, a small amount of gemcitabine may also be incorporated into RNA. Thus, the reduction in the intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon is essentially unable to remove gemcitabine and repair the growing DNA strands. After gemcitabine is incorporated into DNA, one additional nucleotide is added to the growing DNA strands. After this addition there is essentially a complete inhibition in further DNA synthesis (masked chain termination). After incorporation into DNA, gemcitabine then appears to induce the programmed cellular death process known as apoptosis.

Clinical data:

Bladder cancer:?A randomised phase III study of 405 patients with advanced or metastatic urothelial transitional cell carcinoma showed no difference between the two treatment arms, gemcitabine/cisplatin versus methotrexate/vinblastine/adriamycin/cisplatin (MVAC), in terms of median survival (12.8 and 14.8 months respectively, p=0.547), time to disease progression (7.4 and 7.6 months respectively, p=0.842) and response rate (49.4% and 45.7% respectively, p=0.512). However, the combination of gemcitabine and cisplatin had a better toxicity profile than MVAC.

Pancreatic cancer:?In a randomised phase III study of 126 patients with advanced or metastatic pancreatic cancer, gemcitabine showed a statistically significant higher clinical benefit response rate than 5-fluorouracil (23.8% and 4.8% respectively, p=0.0022). Also, a statistically significant prolongation of the time to progression from 0.9 to 2.3 months (log-rank p<0.0002) and a statistically significant prolongation of median survival from 4.4 to 5.7 months (log-rank p<0.0024) was observed in patients treated with gemcitabine compared to patients treated with 5-fluorouracil.

Non small cell lung cancer:?In a randomised phase III study of 522 patients with inoperable, locally advanced or metastatic NSCLC, gemcitabine in combination with cisplatin showed a statistically significant higher response rate than cisplatin alone (31.0% and 12.0%, respectively, p<0.0001). A statistically significant prolongation of the time to progression, from 3.7 to 5.6 months (log-rank p<0.0012) and a statistically significant prolongation of median survival from 7.6 months to 9.1 months (log-rank p<0.004) was observed in patients treated with gemcitabine/cisplatin compared to patients treated with cisplatin.

In another randomised phase III study of 135 patients with stage IIIB or IV NSCLC, a combination of gemcitabine and cisplatin showed a statistically significant higher response rate than a combination of cisplatin and etoposide (40.6% and 21.2%, respectively, p=0.025). A statistically significant prolongation of the time to progression, from 4.3 to 6.9 months (p=0.014) was observed in patients treated with gemcitabine/cisplatin compared to patients treated with etoposide/cisplatin.

In both studies it was found that tolerability was similar in the two treatment arms.

Ovarian carcinoma:?In a randomised phase III study, 356 patients with advanced epithelial ovarian carcinoma who had relapsed at least 6 months after completing platinum based therapy were randomised to therapy with gemcitabine and carboplatin (GCb), or carboplatin (Cb). A statistically significant prolongation of the time to progression of disease, from 5.8 to 8.6 months (log-rank p= 0.0038) was observed in the patients treated with GCb compared to patients treated with Cb. Differences in response rate of 47.2% in the GCb arm versus 30.9% in the Cb arm (p=0.0016) and median survival 18 months (GCb) versus 17.3 (Cb) (p=0.73) favoured the GCb arm.

Breast cancer:?In a randomised phase III study of 529 patients with inoperable, locally recurrent or metastatic breast cancer with relapse after adjuvant/neoadjuvant chemotherapy, gemcitabine in combination with paclitaxel showed a statistically significant prolongation of time to documented disease progression from 3.98 to 6.14 months (log-rank p=0.0002) in patients treated with gemcitabine/paclitaxel compared to patients treated with paclitaxel. After 377 deaths, the overall survival was 18.6 months versus 15.8 months (log rank p=0.0489, HR 0.82) in patients treated with gemcitabine/paclitaxel compared to patients treated with paclitaxel and the overall response rate was 41.4% and 26.2% respectively (p= 0.0002).

5.2 Pharmacokinetic properties

The pharmacokinetics of gemcitabine have been examined in 353 patients in seven studies. The 121 women and 232 men ranged in age from 29 to 79 years. Of these patients, approximately 45% had non-small cell lung cancer and 35% were diagnosed with pancreatic cancer. The following pharmacokinetic parameters were obtained for doses ranging from 500 to 2,592 mg/m2?that were infused from 0.4 to 1.2 hours.

Peak plasma concentrations (obtained within 5 minutes of the end of the infusion) were 3.2 to 45.5 ?g/ml. Plasma concentrations of the parent compound following a dose of 1,000 mg/m2/30-minutes are greater than 5 ?g/ml for approximately 30-minutes after the end of the infusion, and greater than 0.4 ?g/ml for an additional hour.

Distribution

The volume of distribution of the central compartment was 12.4 l/m2?for women and 17.5 l/m2?for men (inter-individual variability was 91.9%). The volume of distribution of the peripheral compartment was 47.4 l/m2. The volume of the peripheral compartment was not sensitive to gender.

The plasma protein binding was considered to be negligible.

Half-life:?This ranged from 42 to 94 minutes depending on age and gender. For the recommended dosing schedule, gemcitabine elimination should be virtually complete within 5 to 11 hours of the start of the infusion. Gemcitabine does not accumulate when administered once weekly.

Metabolism:

Gemcitabine is rapidly metabolised by cytidine deaminase in the liver, kidney, blood, and other tissues.

Intracellular metabolism of gemcitabine produces the gemcitabine mono, di, and triphosphates (dFdCMP, dFdCDP, and dFdCTP), of which dFdCDP and dFdCTP are considered active. These intracellular metabolites have not been detected in plasma or urine.

The primary metabolite, 2′-deoxy-2′,2′-difluorouridine (dFdU), is not active and is found in plasma and urine.

Excretion:

Systemic clearance ranged from 29.2 l/hr/m2?to 92.2 l/hr/m2?depending on gender and age (inter-individual variability was 52.2%). Clearance for women is approximately 25% lower than the values for men. Although rapid, clearance for both men and women appears to decrease with age. For the recommended gemcitabine dose of 1,000 mg/m2?given as a 30 minute infusion, lower clearance values for women and men should not necessitate a decrease in the gemcitabine dose.

Urinary excretion:?Less than 10% is excreted as unchanged drug.

Renal clearance was?2 to 7 l/hr/m2.

During the week following administration, 92 to 98% of the dose of gemcitabine administered is recovered, 99% in the urine, mainly in the form of dFdU and 1% of the dose is excreted in faeces.

dFdCTP Kinetics:

This metabolite can be found in peripheral blood mononuclear cells and the information below refers to these cells.

Intracellular concentrations increase in proportion to gemcitabine doses of 35-350 mg/m2/30 min, which give steady-state concentrations of 0.4-5 ?g/ml. At gemcitabine plasma concentrations above 5 ?g/ml, dFdCTP levels do not increase, suggesting that the formation is saturable in these cells.

Half-life of terminal elimination: 0.7-12 hours.

dFdU Kinetics:

Peak plasma concentrations (3-15 minutes after end of 30 minute infusion, 1,000 mg/m2):

28-52?g/ml.

Trough concentration following once weekly dosing:

0.07-1.12 ?g/ml, with no apparent accumulation.

Triphasic plasma concentration versus time curve, mean half-life of terminal phase:

65 hours (range 33-84 hours).

Formation of dFdU from parent compound:

91%-98%.

Mean volume of distribution of central compartment:

18 l/m2?(range 11-22 l/m2).

Mean steady-state volume of distribution (Vss):

150 l/m2?(range 96-228 l/m2).

Tissue distribution:

Extensive.

Mean apparent clearance:

2.5 l/hr/m2?(range 1-4 l/hr/m2).

Urinary excretion:

All.

Gemcitabine and Paclitaxel Combination Therapy:

Combination therapy did not alter the pharmacokinetics of either gemcitabine or paclitaxel.

Gemcitabine and Carboplatin Combination Therapy:

When given in combination with carboplatin the pharmacokinetics of gemcitabine were not altered.

Renal impairment:

Mild to moderate renal insufficiency (GFR from 30 ml/min to 80 ml/min) has no consistent,

significant effect on gemcitabine pharmacokinetics.

5.3 Preclinical safety data

In repeated dose studies of up to 6 months duration in mice and dogs, the principal finding was schedule and dose-dependent haematopoetic suppression, which was reversible. Gemcitabine showed mutagenic potential in an?in-vitro?mutation test and in an?in-vivo?bone marrow micronucleus test. Long-term animal studies have not been conducted to evaluate the carcinogenic potential of gemcitabine.

In fertility studies, gemcitabine caused reversible hypospermatogenesis in male mice. No effect on the fertility of females has been detected.

Evaluation of experimental animal studies has shown reproductive toxicity e.g. birth defects and other effects on the development of the embryo or foetus, the course of gestation or peri- and postnatal development.

6.PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol

Sodium acetate trihydrate

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal product except those mentioned in section 6.6.

6.3 Shelf life

As packaged for sale:

2 years

After reconstitution:

Chemical and physical in-use stability has been demonstrated for 35 days at 25?C.

From a microbiological point of view, the product should be used immediately.

Solutions should not be refrigerated, as crystallisation may occur.

6.4 Special precautions for storage

As packaged for sale:

This medicinal product does not require any special storage conditions.

In-use:

For storage condition of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I clear glass vial with bromobutyl stopper. Vials may be sheathed in protective ONCO-TAIN sleeves.

Pack sizes: carton containing a single vial or packs of 5 single vial cartons. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Reconstitution:

For single use only

This medicinal product has only been shown to be compatible with sodium chloride 9 mg/ml (0.9%) solution for injection. Accordingly, only this diluent should be used for reconstitution. Compatibility with other active substances has not been studied. Therefore, it is not recommended to mix this medicinal product with other active substances when reconstituted.

Reconstitution at concentrations greater than 38 mg/ml may result in incomplete dissolution, and should be avoided.

To reconstitute, slowly add the appropriate volume of sodium chloride 9 mg/ml (0.9%) solution for injection (as stated in the table below) and shake to dissolve.

PresentationVolume of sodium chloride 9 mg/ml (0.9%) solution for injection to be addedDisplacement volumeFinal concentration
200 mg5 ml0.26 ml38 mg/ml
1 g25 ml1.3 ml38 mg/ml
2 g50 ml2.6 ml38 mg/ml

The appropriate amount of medicinal product may be further diluted with sodium chloride 9 mg/ml (0.9%) solution for injection.

Parenteral medicinal products should be inspected visually for particulate matter and discolouration, prior to administration, whenever solution and container permit.

Any unused solution should be discarded as described below.

Guidelines for the Safe Handling of Cytotoxic Medicinal Products:

Local guidelines on safe preparation and handling of cytotoxic medicinal products must be adhered to. Cytotoxic preparations should not be handled by pregnant staff. The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicines used. This should be performed in a designated area. The work surface should be covered with disposable plastic-backed absorbent paper.

Suitable eye protection, disposable gloves, face mask and disposable apron should be worn. Precautions should be taken to avoid the medicinal product accidentally coming into contact with the eyes. If accidental contamination occurs, the eye should be washed with water thoroughly and immediately.

Syringes and infusion sets should be assembled carefully to avoid leakage (use of Luer lock fittings is recommended). Large bore needles are recommended to minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.

Actual spillage or leakage should be mopped up wearing protective gloves. Excreta and vomit must be handled with care.

Disposal:

Adequate care and precaution should be taken in the disposal of items used to reconstitute this medicinal product. Any unused dry product or contaminated materials should be placed in a high-risk waste bag. Sharp objects (needles, syringes, vials, etc) should be placed in a suitable rigid container. Personnel concerned with the collection and disposal of this waste should be aware of the hazard involved. Waste material should be destroyed by incineration. Any unused product or waste material should be disposed of in accordance with local requirements.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
Mumbai, India
Survey No.188/1 to 189/1,190/1 to 4,
Athiyawad, Dabhel,
Daman- 396210 (INDIA)

Gemcitabine Powder for Solution for Infusion IP 200mg Taj Pharma
Package leaflet: Information for the patient

Gemcitabine

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

  1. What Gemcitabine is and what it is used for
  2. What you need to know before you take Gemcitabine
  3. How to take Gemcitabine
  4. Possible side effects
  5. How to store Gemcitabine
  6. Contents of the pack and other information
1 WHAT GEMCITABINE IS AND WHAT IT IS USED FOR

Gemcitabine Inj belongs to a group of medicines called ?cytotoxics?. These medicines kill dividing cells, including cancer cells.

Gemcitabine may be given alone or in combination with other anti-cancer medicines, depending on the type of cancer you have. Gemcitabine Inj is used in the treatment of a number of types of cancer including:
?? non-small cell lung cancer (NSCLC), alone or together with cisplatin
?? pancreatic cancer
?? breast cancer, together with paclitaxel
?? ovarian cancer, together with carboplatin
?? bladder cancer, together with cisplatin

2 WHAT YOU NEED TO KNOW BEFORE YOU TAKE GEMCITABINE

You should not be given Gemcitabine Inj
?If you are allergic to gemcitabine or any of the other ingredients of this medicine (listed in section 6).
?If you are breast-feeding.

Tell the doctor if you think any of the above applies to you.

Warnings and precautions
Before the first infusion you will have samples of your blood taken to evaluate if you have sufficient kidney and liver function. Before each infusion you will also have samples of your blood taken to check if you have enough blood cells to receive Gemcitabine. Your doctor may decide to change your dose or delay treating you, depending on your general condition and if your blood cell counts are too low. Periodically you will have samples of your blood taken to check your kidney and liver function.

Talk to your doctor or nurse before using Gemcitabine if:
?? you have, or have previously had liver disease, heart disease or vascular disease.
?? you have recently had, or are going to have radiotherapy.
? you have been vaccinated recently.
? you develop breathing difficulties or feel very weak and are very pale (this may be a sign of lung problems or kidney failure).

Other medicines and Gemcitabine Inj
Tell your doctor if you are taking, have recently taken or might take any other medicines, including vaccinations.

Pregnancy, breast-feeding and fertility
If you are pregnant, or thinking about becoming pregnant, tell your doctor. The use of Gemcitabine Inj should be avoided if pregnant. Your doctor will discuss with you the potential risk of taking Gemcitabine Inj during pregnancy.

If you are breast-feeding, tell your doctor. You must discontinue breast-feeding during treatment with Gemcitabine Inj.
Men are advised not to father a child during, and up to 6 months after treatment with gemcitabine. If you would like to father a child during the treatment or in the 6 months following treatment, please seek advice from your doctor or pharmacist. You may want to seek counselling on sperm storage before starting your therapy.

Driving and using machines
Gemcitabine treatment can make you feel drowsy. Alcohol can make this worse. Do not drive or operate machinery until you are sure that Gemcitabine Inj has not made you feel sleepy.

Gemcitabine Inj contains sodium
This medicinal product contains 35 mg (1.5 mmol) of sodium per 2 g dose. This should be taken into consideration by patients on a controlled sodium diet.

3 HOW TO TAKE GEMCITABINE

The usual dose of Gemcitabine Inj is 1000-1250 mg for every square metre of your body?s surface area. Your height and weight are measured to work out the surface area of your body. Your doctor will use this body surface area to work out the right dose for you. This dosage may be adjusted, or treatment may be delayed depending on your blood cell counts and on your general condition.

How frequently you receive your infusion will depend on the type of cancer you are being treated for.

A hospital pharmacist or doctor will have dissolved the Gemcitabine Inj powder before it is given to you.

You will always receive Gemcitabine Inj by infusion into one of your veins. The infusion will last approximately 30 minutes.

If you have further questions on the use of this product ask your doctor or pharmacist.

4 POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Frequencies of the observed side effects are defined as:
?? very common: affects more than 1 user in 10
?? common: affects 1 to 10 users in 100
?? uncommon: affects 1 to 10 users in 1,000
?? rare: affects 1 to 10 users in 10,000
?? very rare: affects less than 1 user in 10,000
?? not known: the frequency cannot be estimated from the available data

?If any of the following happen, tell your doctor immediately:

  • Fever or infection (common): if you have a temperature of 38?C or greater, sweating or other signs of infection (since you might have less white blood cells than normal which is very common).
    ? Irregular heart rate (arrhythmia) (uncommon).
    ? Pain, redness, swelling or sores in your mouth (common).
    ?? Allergic reactions: if you develop skin rash (very common) / itching (common), or fever (very common).
    ? Tiredness, feeling faint, becoming easily breathless or if you look pale (since you? might have less haemoglobin than normal which is very common).
    ? Bleeding from the gums, nose or mouth or any bleeding that would not stop, reddish or pinkish urine, unexpected bruising (since you might have less platelets than normal which is very common).
    ? Difficulty breathing (it is very common to have mild breathing difficulty soon? after receiving a gemcitabine infusion but which soon passes; however uncommonly or rarely there can be more severe lung problems).
    ? Tiredness, looking pale, bruising easily and kidney problems which your doctor will do blood tests to investigate (uncommon).
    ? Worsening skin rash with sloughing of skin rash and severe skin blistering? together with mouth sores (very rare).

Side effects that you might experience when taking Gemcitabine Inj include:

Very common side effects (affecting more than 1 user in 10):
?Low haemoglobin levels (anaemia)
?? Low white blood cells
?? Low platelet count
?? Difficulty breathing
?? Vomiting
?? Nausea
?? Skin rash (an allergic skin rash which is frequently itchy)
?? Hair loss
?? Liver problems: found through abnormal blood test results
?? Blood in the urine
?? Abnormal urine tests: protein in urine
?? Flu like symptoms (including fever)
?? Oedema (swelling of ankles, fingers, feet and face)

Common side effects (affecting 1 to 10 users in 100):
?Fever, accompanied by a low white blood cell count (febrile neutropaenia)
?? Anorexia (poor appetite)
?? Headache
?? Drowsiness
?? Difficulty sleeping (insomnia)
?? Cough
?? Runny nose or nasal congestion
?? Diarrhoea
?? Constipation
?? Pain, redness, swelling or sores in the mouth
?? Itching
? ?Sweating
?? Muscle pain
?? Back pain
?? Weakness
?? Chills

Uncommon side effects (affecting 1 to 10 users in 1,000):
?Stroke
?? Irregular heart beat (arrhythmia)
?? Heart failure
?? Interstitial pneumonitis (scarring of the air sacs of the lung)
?? Spasm of the airways (wheezing)
?? Abnormal chest X ray/scan (which show scarring of the lungs)
?? Serious liver damage, including liver failure
?? Kidney failure

Rare side effects (affecting 1 to 10 users in 10,000):
?Heart attack (myocardial infarction)
?? Gangrene of fingers or toes
?? Low blood pressure
?? Fluid in the lungs
?? Adult Respiratory Distress Syndrome (severe lung inflammation causing? respiratory failure)
? Skin shedding
?? Skin blisters
?? Skin sores (ulcers)
?? Soreness at the injection site after the injection
?? Radiation toxicity (scarring of the air sacs of the lung associated with radiation? therapy)
? Radiation recall (a skin rash like severe sunburn which can occur on skin that has previously been exposed to radiotherapy)

Very rare (affects less than 1 user in 10,000):
? Increased platelet count
?? Ischaemic colitis (inflammation of the lining of the large bowel, caused by? reduced blood supply)
? Anaphylactic reaction (severe hypersensitivity/allergic reaction)
?? Sloughing of skin and severe skin blistering
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet.

5 HOW TO STORE GEMCITABINE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the vial and carton after EXP. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
From a microbiological point of view
After reconstitution: This medicine may be stored for 35? C days at 25 however, it is advised that the product is used immediately.
The reconstituted solution should not be refrigerated.
The prepared solution for infusion should not be used if it contains particles or if it is strongly coloured.
This medicine will be prepared and administered to you by healthcare staff. Any unused medicine will be disposed of by healthcare staff, according to local procedures.

6 CONTENTS OF THE PACK AND OTHER INFORMATION

What Gemcitabine contains

The active substance is gemcitabine (as hydrochloride)

a) Each sterile lyophilized vial contains
Gemcitabine Hydrochloride IP
Equivalent to Gemcitabine??? 200mg
Mannitol??????????????????? 200mg
Sodium Acetate????????? 12.5mg
Sodium Hydroxide?? q.s.
Hydroxide Acid??????? q.s.

b) Each sterile lyophilized vial contains
Gemcitabine Hydrochloride IP
Equivalent to Gemcitabine 1000mg
Mannitol??????????? 1000mg
Sodium Acetate?? 5mg
Sodium Hydroxide?? q.s.
Hydroxide Acid????? q.s.

– The other ingredients are mannitol, sodium acetate trihydrate, hydrochloric acid (for pH adjustment) and sodium hydroxide (for pH adjustment)
– One ml of the reconstituted solution for infusion contains 38 mg gemcitabine (as hydrochloride)

Contents of the pack

Gemcitabine tablets are oval-shaped tablet.
Each 28 day carton contains 56 film-coated tablets in 4 cardboard wallets of 14 film-coated tablets each.
Each 30 day carton contains 60 film-coated tablets in 5 cardboard wallets of 12 film-coated tablets each.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
Mumbai, India
at SURVEY NO. 188/1, 190/1TO 4, ATHIYAWAD , DABHEL,
DAMAN- 396210 (INDIA)

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