Gemcitabine  USP 1000 mg powder for solution for injection Taj Pharma

  1. Name of the medicinal product

Gemcitabine  USP 200 mg powder for solution for injection Taj Pharma
Gemcitabine  USP 1000 mg powder for solution for injection Taj Pharma

  1. Qualitative and quantitative composition

a) Gemcitabine  USP 200 mg powder for solution for injection Taj Pharma
Each sterile lyophilized vial contains
Gemcitabine hydrochloride USP
Equivalent to Gemitabine               200mg
Mannitol USP                                  1000mg
Sodium Acetate USP                      62.5mg
Sodium Hydroxide USPNF               q.s.
Hydrochloric Acid USPNF                 q.s.

b) Gemcitabine  USP 1000 mg powder for solution for injection Taj Pharma
Each sterile lyophilized vial contains
Gemcitabine hydrochloride USP
Equivalent to Gemitabine                1000mg
Mannitol USP                                  1000mg
Sodium Acetate USP                       62.5mg
Sodium Hydroxide USPNF                q.s.
Hydrochloric Acid USPNF                  q.s.

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Powder for solution for injection.

  1. Clinical particulars

4.1 Therapeutic indications

Gemcitabine is indicated for the treatment of locally advanced or metastatic bladder cancer in combination with cisplatin.

Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas.

Gemcitabine, in combination with cisplatin is indicated as first line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine monotherapy can be considered in elderly patients or those with performance status 2.

Gemcitabine is indicated for the treatment of patients with 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.

Gemcitabine, in combination with paclitaxel, is indicated for the treatment of patients with unresectable, locally recurrent or metastatic breast cancer who have relapsed following adjuvant/neoadjuvant chemotherapy. Prior chemotherapy should have included an anthracycline unless clinically contraindicated.

4.2 Posology and method of administration

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

Posology

Bladder cancer

Combination use

The recommended dose for gemcitabine is 1000 mg/m2, given by 30-minute injection. 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 4-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.

Pancreatic cancer

The recommended dose of gemcitabine is 1000 mg/m2, given by 30-minute intravenous injection. This should be repeated once weekly for up to 7 weeks followed by a week of rest. Subsequent cycles should consist of injections once weekly for 3 consecutive weeks out of every 4 weeks. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.

Non small cell lung cancer

Monotherapy

The recommended dose of gemcitabine is 1000 mg/m2, given by 30-minute intravenous injection. This should be repeated once weekly for 3 weeks, followed by a 1-week rest period. This 4-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.

Combination use

The recommended dose for gemcitabine is 1250 mg/m2 body surface area given as a 30-minute intravenous injection on Day 1 and 8 of the treatment cycle (21 days). Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient. Cisplatin has been used at doses between 75-100 mg/m2 once every 3 weeks.

Breast cancer

Combination use

Gemcitabine in combination with paclitaxel is recommended using paclitaxel (175 mg/m2) administered on Day 1 over approximately 3-hours as an intravenous injection, followed by gemcitabine (1250 mg/m2) as a 30-minute intravenous injection on Days 1 and 8 of each 21-day cycle. Dose reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient. Patients should have an absolute granulocyte count of at least 1,500 (x 106/l) prior to initiation of gemcitabine + paclitaxel combination.

Ovarian cancer

Combination use

Gemcitabine in combination with carboplatin is recommended using gemcitabine 1000 mg/m2 administered on Days 1 and 8 of each 21-day cycle as a 30-minute intravenous injection. After gemcitabine, carboplatin will be given on Day 1 consistent with a target Area under curve (AUC) of 4.0 mg/ml-min. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.

Monitoring for toxicity and dose modification due to toxicity

Dose modification 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 grade 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 resolved in the opinion of the physician.

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

Dose modification due to haematological toxicity

Initiation of a cycle

For all indications, the patient must be monitored before each dose for platelet and granulocyte counts. Patients should have an absolute granulocyte count of at least 1,500 (x 106/l) and platelet count of 100,000 (x 106/l) prior to the initiation 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, NSCLC and pancreatic cancer, given in monotherapy or in combination with cisplatin
Absolute granulocyte count

(x 106/l)

Platelet count

(x 106/l)

Percentage of standard dose of Gemcitabine (%)
> 1,000 and > 100,000 100
500-1,000 or 50,000-100,000 75
<500 or < 50,000 Omit dose *

* Treatment omitted will not be re-instated within a cycle before the absolute granulocyte count reaches at least 500 (x106/l) and the platelet count reaches 50,000 (x106/l).

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

(x 106/l)

Platelet count

(x 106/l)

Percentage of standard dose of Gemcitabine (%)
> 1,200 and >75,000 100
1,000-<l,200 or 50,000-75,000 75
700-<l,000 and ≥ 50,000 50
<700 or <50,000 Omit dose*

* Treatment omitted will not be re-instated within a cycle. Treatment will start on day 1 of the next cycle once the absolute granulocyte count reaches at least 1,500 (x106/l) and the platelet count reaches 100,000 (x106/l).

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

(x 106/l)

Platelet count

(x 106/l)

Percentage of standard dose of Gemcitabine (%)
> 1,500 and ≥ 100,000 100
1000-1,500 or 75,000-100,000 50
<1000 or < 75,000 Omit dose*

* Treatment omitted will not be re-instated within a cycle. Treatment will start on day 1 of the next cycle once the absolute granulocyte count reaches at least 1,500 (x106/l) and the platelet count reaches 100,000 (x106/l).

Dose modifications 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 < 500 x 106/l for more than 5 days
  • Absolute granulocyte count < 100 x 106/l for more than 3 days
  • Febrile neutropaenia
  • Platelets < 25,000 x106/l
  • Cycle delay of more than 1 week due to toxicity

Method of administration

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

For instructions on reconstitution, of the medicinal product before administration, see section 6.6.

Special populations

Patients with renal or hepatic 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).

Older people (> 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 older people (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 the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Prolongation of the injection time and increased dosing frequency have been shown to increase toxicity.

Haematological toxicity

Gemcitabine can suppress bone marrow function as manifested by leucopaenia, thrombocytopaenia and anaemia.

Patients receiving gemcitabine should be monitored prior to each dose for platelet, leucocyte and granulocyte counts. Suspension or modification of therapy should be considered when drug-induced bone marrow depression is detected (see section 4.2). However, myelosuppression is short lived and usually does not result in dose reduction and rarely in discontinuation.

Peripheral blood counts may continue to deteriorate after gemcitabine administration has been stopped. In patients with impaired bone marrow function, the treatment should be started with caution.

As with other cytotoxic treatments, the risk of cumulative bone-marrow suppression must be considered when gemcitabine treatment is given together with other chemotherapy

Hepatic and renal impairment

Gemcitabine should be used with caution in patients with hepatic or renal function impairment as there is insufficient information from clinical studies to allow clear dose recommendation for this patient population (see section 4.2).

Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism or liver cirrhosis may lead to exacerbation of the underlying hepatic impairment.

Laboratory evaluation of renal and hepatic function (including virological tests) should be performed periodically.

Concomitant radiotherapy

Concomitant radiotherapy (given together or ≤ 7 days apart): Toxicity has been reported (see section 4.5 for details and recommendations for use).

Live vaccinations

Yellow fever vaccine and other live attenuated vaccines are not recommended in patients treated with gemcitabine (see section 4.5).

Posterior reversible encephalopathy syndrome

Reports of posterior reversible encephalopathy syndrome (PRES) with potentially severe consequences have been reported in patients receiving gemcitabine as single agent or in combination with other chemotherapeutic agents. Acute hypertension and seizure activity were reported in most gemcitabine patients experiencing PRES, but other symptoms such as headache, lethargy, confusion and blindness could also be present. Diagnosis is optimally confirmed by magnetic resonance imaging (MRI). PRES was typically reversible with appropriate supportive measures. Gemcitabine should be permanently discontinued and supportive measures implemented, including blood pressure control and anti-seizure therapy, if PRES develops during therapy.

Cardiovascular

Due to the risk of cardiac and/or vascular disorders with gemcitabine, particular caution must be exercised with patients presenting a history of cardiovascular events.

Capillary leak syndrome

Capillary leak syndrome has been reported in patients receiving gemcitabine as single agent or in combination with other chemotherapeutic agents (see section 4.8). The condition is usually treatable if recognised early and managed appropriately, but fatal cases have been reported. The condition involves systemic capillary hyperpermeability during which fluid and proteins from the intravascular space leak into the interstitium. The clinical features include generalised oedema, weight gain, hypoalbuminaemia, severe hypotension, acute renal impairment and pulmonary oedema. Gemcitabine should be discontinued and supportive measures implemented if capillary leak syndrome develops during therapy. Capillary leak syndrome can occur in later cycles and has been associated in the literature with adult respiratory distress syndrome.

Pulmonary

Pulmonary effects, sometimes severe (such as pulmonary oedema, interstitial pneumonitis or adult respiratory distress syndrome (ARDS)) have been reported in association with gemcitabine therapy.

If such effects develop, consideration should be made to discontinuing gemcitabine therapy. Early use of supportive care measure may help ameliorate the condition.

Renal

Haemolytic uraemic syndrome

Clinical findings consistent with the haemolytic uraemic syndrome (HUS) were rarely reported (post- marketing data) in patients receiving gemcitabine (see section 4.8). HUS is a potentially life-threatening disorder. Gemcitabine should be discontinued at the first signs of any evidence of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopaenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH. Renal failure may not be reversible with discontinuation of therapy and dialysis may be required.

Fertility

In fertility studies gemcitabine caused hypospermatogenesis in male mice (see section 5.3). Therefore, men being treated with gemcitabine are advised not to father a child during and up to 6 months after treatment and to seek further advice regarding cryoconservation of sperm prior to treatment because of the possibility of infertility due to therapy with gemcitabine (see section 4.6).

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed (see section 5.2)

Radiotherapy

Concurrent (given together or ≤ 7 days apart) – Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of gemcitabine, frequency of gemcitabine administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. Pre-clinical and clinical studies have shown that gemcitabine has radiosensitising activity. In a single trial, where gemcitabine at a dose of 1,000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life threatening mucositis, especially oesophagitis, and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4,795 cm3]. Studies done subsequently have suggested that it is feasible to administer gemcitabine at lower doses with concurrent radiotherapy with predictable toxicity, such as a phase II study in non-small cell lung cancer, where thoracic radiation doses of 66 Gy were applied concomitantly with an administration with gemcitabine (600 mg/m2, four times) and cisplatin (80 mg/m2 twice) during 6 weeks. The optimum regimen for safe administration of gemcitabine with therapeutic doses of radiation has not yet been determined in all tumour types.

Non-concurrent (given >7 days apart)- Analysis of the data does not indicate any enhanced toxicity when gemcitabine is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that gemcitabine can be started after the acute effects of radiation have resolved or at least one week after radiation.

Radiation injury has been reported on targeted tissues (e.g. oesophagitis, colitis, and pneumonitis) in association with both concurrent and non-concurrent use of gemcitabine.

Others

Yellow fever and other live attenuated vaccines are not recommended due to the risk of systemic, possibly fatal, disease, particularly in immunosuppressed patients.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of gemcitabine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Based on results from animal studies and the mechanism of action of gemcitabine, this substance should not be used during pregnancy unless clearly necessary. Women should be advised not to become pregnant during treatment with gemcitabine and to warn their attending physician immediately, should this occur after all.

Breast-feeding

It is not known whether gemcitabine is excreted in human milk and adverse effects on the suckling child cannot be excluded. Breast-feeding must be discontinued during gemcitabine therapy.

Fertility

In fertility studies gemcitabine caused hypospermatogenesis in male mice (see section 5.3). Therefore, men being treated with gemcitabine are advised not to father a child during and up to 6 months after treatment and to seek further advice regarding cryoconservation of sperm prior to treatment because of the possibility of infertility due to therapy with gemcitabine.

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 drug reactions associated with Gemcitabine treatment include: nausea with or without vomiting, raised liver transaminases (AST/ALT) and alkaline phosphatase, reported in approximately 60% of patients; proteinuria and haematuria reported in approximately 50% patients; dyspnoea reported in 10-40% of patients (highest incidence in lung cancer patients); allergic skin rashes occur 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, injection 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 (≥ l/10), Common (≥ l/100 to <1/10), Uncommon (≥ l/1000 to <1/100), Rare (≥ l/10,000 to <1/1000), Very Rare (<1/10,000), Not known (cannot be estimated from the available data).

The following table of undesirable effects and frequencies is based on data from clinical trials. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class Frequency grouping
Infections and infestations Common

• Infections

Not known

• Sepsis

Blood and lymphatic system disorders Very common

• Leucopaenia (Neutropaenia Grade 3 = 19.3%; Grade 4 = 6%).

Bone-marrow suppression is usually mild to moderate and mostly affects the granulocyte count (see section 4.2 and 4.4)

• Thrombocytopaenia

• Anaemia

Common

• Febrile neutropaenia

Very rare

• Thrombocytosis

• Thrombotic microangiopathy

Immune system disorders Very rare

• Anaphylactoid reaction

Metabolism and nutrition disorders Common

• Anorexia

Nervous system disorders Common

• Headache

• Insomnia

• Somnolence

Uncommon

• Cerebrovascular accident

Very rare

Posterior reversible encephalopathy syndrome (see section 4.4.)

Cardiac disorders Uncommon

• Arrhythmias, predominantly supraventricular in nature

• Heart failure

Rare

• Myocardial infarct

Vascular disorders Rare

• Clinical signs of peripheral vasculitis and gangrene

• Hypotension

Very rare

Capillary leak syndrome (see section 4.4)

Respiratory, thoracic and mediastinal disorders Very 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 disorders Very common

• Vomiting

• Nausea

Common

• Diarrhoea

• Stomatitis and ulceration of the mouth

• Constipation

Very rare

• Ischaemic colitis

Hepatobiliary disorders Very 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 disorders Very 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

Not known

•Pseudocellulitis

Musculoskeletal and connective tissue disorders Common

• Back pain

• Myalgia

Renal and urinary disorders Very Common

• Haematuria

• Mild proteinuria

Uncommon

• Renal failure (see section 4.4)

• Haemolytic uraemic syndrome (see section 4.4)

General disorders and administration site conditions Very 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 Complications Rare

• 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 3 Grade 4 Grade 3 Grade 4
Laboratory
Anaemia 5 (1.9) 1 (0.4) 15 (5.7) 3 (1.1)
Thrombocytopaenia 0 0 14 (5.3) 1 (0.4)
Neutropaenia 11 (4.2) 17 (6.6)* 82 (31.3) 45 (17.2)*
Non-laboratory
Febrile neutropaenia 3 (1.2) 0 12 (4.6) 1 (0.4)
Fatigue 3 (1.2) 1 (0.4) 15 (5.7) 2 (0.8)
Diarrhoea 5 (1.9) 0 8 (3.1) 0
Motor neuropathy 2 (0.8) 0 6 (2.3) 1 (0.4)
Sensory neuropathy 9 (3.5) 0 14 (5.3) 1 (0.4)

*Grade 4 neutropaenia 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 3 Grade 4 Grade 3 Grade 4
Laboratory
Anaemia 30 (16) 4 (2) 47 (24) 7 (4)
Thrombocytopaenia 15 (8) 25 (13) 57 (29) 57 (29)
Non-laboratory
Nausea and vomiting 37 (19) 3 (2) 44 (22) 0 (0)
Diarrhoea 15 (8) 1 (1) 6 (3) 0 (0)
Infection 19 (10) 10 (5) 4 (2) 1 (1)
Stomatitis 34 (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 3 Grade 4 Grade 3 Grade 4
Laboratory
Anaemia 10 (5.7) 4 (2.3) 39 (22.3) 9 (5.1)
Neutropaenia 19 (10.9) 2 (1.1) 73 (41.7) 50 (28.6)
Thrombocytopaenia 18 (10.3) 2 (1.1) 53 (30.3) 8 (4.6)
Leucopaenia 11 (6.3) 1 (0.6) 84 (48.0) 9 (5.1)
Non-laboratory
Haemorrhage 0 (0.0) 0 (0.0) 3 (1.8) (0.0)
Febrile neutropaenia 0 (0.0) 0 (0.0) 2 (1.1) (0.0)
Infection without neutropaenia 0 (0) 0 (0.0) (0.0) 1 (0.6)

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

There is no known antidote for overdose of gemcitabine. Doses as high as 5700 mg/m2 have been administered by intravenous injection over 30-minutes every 2 weeks with clinically acceptable toxicity. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and receive supportive therapy, as necessary.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: pyrimidine analogues

Cytotoxic activity in cell cultures

Gemcitabine shows significant cytotoxic effects against a variety of cultured murine and human tumour cells. Its action is phase-specific such that gemcitabine primarily kills cells that are undergoing DNA synthesis (S-phase) and, under certain circumstances, blocks the progression of cells at the junction of the G1/S phase boundary. In vitro, the cytotoxic effect of gemcitabine is dependent on both concentration and time.

Antitumoral activity in preclinical models

In animal tumour models, antitumoural activity of gemcitabine is schedule-dependent. When gemcitabine is administered daily, high mortality among the animals but minimal antitumoural activity is observed. 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.

Mechanism of action

Cellular metabolism and mechanism 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 effect of gemcitabine is due to inhibition of DNA synthesis by two mechanisms of action by dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase, which is uniquely responsible for catalysing the reactions that produce deoxynucleoside triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme by dFdCDP reduces the concentration of deoxynucleosides in general and, in particular, 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 reduced intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon lacks the ability to eliminate gemcitabine and to 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 appears to induce the programmed cell 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 injection) were 3.2 to 45.5 µg/ml. Plasma concentrations of the parent compound following a dose of 1,000 mg/m2/30-minutes are greater than 5 µg/ml for approximately 30-minutes after the end of the injection, and greater than 0.4 µg/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 injection. 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 /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 1000 mg/m2 given as a 30-minute injection, 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-minutes, which give steady state concentrations of 0.4-5 µg/ml. At gemcitabine plasma concentrations above 5 µg/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 injection, 1000 mg/m2): 28-52 µg/ml.

Trough concentration following once weekly dosing: 0.07-1.12 µg/ml, with no apparent accumulation.

Triphasic plasma concentration versus time curve, mean half-life of terminal phase – 65 hours (range 33-84 hr).

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 repeat-dose studies of up to 6 months in duration in mice and dogs, the principal finding was schedule and dose-dependent haematopoietic suppression which was reversible.

Gemcitabine is mutagenic in an in vitro mutation test and an in vivo bone marrow micronucleus test. Long term animal studies evaluating the carcinogenic potential have not been performed.

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.

  1. Pharmaceutical particulars

6.1 List of excipients

Mannitol USP, Sodium acetate USP, Sodium hydroxide USPNF, Hydrochloric acid USPNF.

6.2 Incompatibilities

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

6.3 Shelf life

As packaged for sale:

36 months.

After reconstitution:

Chemical and physical in-use stability has been demonstrated for 24 hours at 30°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 30°C.

Reconstituted gemcitabine should not be refrigerated, as this results in crystallisation.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Gemcitabine 1000 mg powder for injection

50 ml glass vial colourless type-I moulded glass vial with bromobutyl rubber stopper and with 20 mm crimp.

Pack size: 1 vial of 50 ml.

6.6 Special precautions for disposal and other handling

Reconstituting the solution

Physiological saline solution without preservative agents is the only diluent approved for reconstituting gemcitabine injection. Although incompatibilities have not been observed, mixing gemcitabine with other substances during reconstitution or administration is not recommended. Following dilution, the upper gemcitabine concentration limit is 38 mg/ml. Dilution to concentrations above 38 mg/ml may result in incomplete dissolution and should be avoided.

To reconstitute the product, 5 ml (min.) or 25 ml (min.) of 0.9% physiological saline solution is added to the 200 mg vial or 1 g vial, respectively (both yielding a final concentration of 38 mg/ml and a displacements volume of 0.26 ml or 1.3 ml respectively). During reconstitution of the solution, the diluent should be added slowly down the side of the vial. Then, shake to dissolve. Further dilution with 0.9% physiological saline solution is possible.

After dilution, the injection should be inspected visually for particulate matter and discolouration. Only clear solutions practically free from suspended particles should be used.

Handling

Standard precautions for reconstituting cytotoxic agents must be observed. The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicines used, in conditions that guarantee the protection of the environment and, particular, the protection of personnel handling the medicines. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area.

Personnel must be provided with appropriate handling materials, notably long sleeved gowns, protection masks, caps, protective goggles, sterile single-use gloves, protective covers for the work area and collection bags for waste.

Cytotoxic preparations should not be handled by pregnant staff.

If the product is allowed to come into contact with the eyes, severe irritation may result. In such an event, the eyes should be washed thoroughly and immediately. Consult a doctor if irritation persists. If the solution should come into contact with skin, rinse the affected area thoroughly with water. Excreta and vomit must be handled with care.

Disposal

All items used for preparation, administration or otherwise coming into contact with gemcitabine should undergo disposal according to hospital standard procedures applicable to cytotoxic agents with due regard to current laws related to the disposal of hazardous waste.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Gemcitabine Taj Pharma USP 1000 mg powder for solution for injection

Package Leaflet: Information for the patient

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 are given Gemcitabine
3. How Gemcitabine is given
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 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.

Gemcitabine is used in the treatment of the following types of cancer:

  • 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.
  1. What you need to know before you are given Gemcitabine

You should not be given Gemcitabine:

  • if you are allergic to gemcitabine or any of the other ingredients of this medicine (listed in section 6)
  • if you are breast-feeding

Warnings and precautions

Talk to your doctor before you are given Gemcitabine.

Before the first injection you will have samples of your blood taken to evaluate if you have sufficient kidney and liver function. Before each injection you will have samples of your blood taken to evaluate if you have enough blood cells to receive Gemcitabine. Your doctor may decide to change the 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 evaluate your kidney and liver function.

Please tell your doctor if:

  • you have, or have previously had liver disease, heart disease, vascular disease or problems with your kidneys as you may not be able to receive Gemcitabine
  • you have recently had, or are going to have radiotherapy as there may be an early or late radiation reaction
  • you have been vaccinated recently
  • you get symptoms such as headache with confusion, seizures (fits) or changes in vision, call your doctor right away. This could be a very rare nervous system side effect named posterior reversible encephalopathy syndrome
  • you develop breathing difficulties or feel very weak and are very pale (may be a sign of kidney failure or problems with your lungs)
  • you develop generalised swelling, shortness of breath or weight gain. This may be a sign of fluid leaking from your small blood vessels into the tissue.

Children and adolescents

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

Other medicines and Gemcitabine

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. The use of Gemcitabine should be avoided during pregnancy. Your doctor will discuss with you the potential risk of taking Gemcitabine during pregnancy.

You must discontinue breast-feeding during Gemcitabine treatment.

Men are advised not to father a child during and up to 6 months following treatment with Gemcitabine. If you would like to father a child during the treatment or in the 6 months following treatment, 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 may make you feel sleepy, particularly if you have consumed any alcohol. Do not drive a car or use machinery until you are sure that Gemcitabine treatment has not made you feel sleepy.

Gemcitabine contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

  1. How Gemcitabine is given

The recommended dose of Gemcitabine 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 Gemcitabine injectiondepends on the type of cancer that you are being treated for.

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

You will always receive Gemcitabine by injectioninto one of your veins. The injectionwill last approximately 30 minutes.

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

  1. Possible side effects

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

You must contact your doctor immediately if you notice any of the following:

Extreme tiredness and weakness, purpura or small areas of bleeding in the skin (bruises), acute renal failure (low urine output or no urine output), and signs of infection. These may be features of thrombotic microangiopathy (clots forming in small blood vessels) and haemolytic uraemic syndrome, which may be fatal.

Tell your doctor about any of the following serious side-effects straight away

Very common: may affect more than 1 in 10 users

  • allergic reactions: if you develop mild to moderate skin rash, or fever
  • 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).

Common: may affect up to 1 in 10 users

  • temperature of 38°C or greater, sweating or other signs of infection (since you might have less white blood cells than normal accompanied by fever also known as febrile neutropenia)
  • pain, redness, swelling or sores in your mouth (stomatitis)
  • allergic reactions: if you develop itching
  • difficulty breathing (it is common to have mild breathing difficulty soon after the Gemcitabine injectionwhich soon passes).

Uncommon: may affect up to 1 in 100 users

  • difficulty breathing (more severe lung problems)
  • irregular heart rate (arrhythmia).

Rare: may affect up to 1 in 1,000 users

  • difficulty breathing (more severe lung problems)
  • severe chest pain (myocardial infarction).

Very rare: may affect up to 1 in 10,000 users

  • severe hypersensitivity/allergic reaction with severe skin rash including red itchy skin, swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), wheezing, fast beating heart and you may feel you are going to faint (anaphylactic reaction)
  • generalised swelling, shortness of breath or weight gain, as you might have fluid leakage from small blood vessels into the tissues (capillary leak syndrome)
  • headache with changes in vision, confusion, seizures or fits (posterior reversible encephalopathy syndrome)
  • severe rash with itching, blistering or peeling of the skin (Stevens-Johnson syndrome, toxic epidermal necrolysis).

Tell your doctor about any of the following side effects as soon as possible

Very common: may affect more than 1 in 10 users

  • low white blood cells
  • difficulty breathing
  • vomiting
  • nausea
  • hair loss
  • liver problems: found through abnormal blood test results
  • blood in urine
  • abnormal urine tests: protein in urine
  • flu like symptoms including fever
  • swelling of ankles, fingers, feet, face (oedema).

Common: may affect up to 1 in 10 users

  • poor appetite (anorexia)
  • headache
  • insomnia
  • sleepiness
  • cough
  • runny nose
  • constipation
  • diarrhoea
  • itching
  • sweating
  • muscle pain
  • back pain
  • fever
  • weakness
  • chills
  • infections.

Uncommon: may affect up to 1 in 100 users

  • scarring of the air sacs of the lung (interstitial pneumonitis)
  • wheeze (spasm of the airways)
  • scarring of the lungs (abnormal chest X ray/scan)
  • heart failure
  • kidney failure
  • serious liver damage, including liver failure
  • stroke.

Rare: may affect up to 1 in 1,000 users

  • low blood pressure
  • skin scaling, ulceration or blister formation
  • sloughing of skin and severe skin blistering
  • injection site reactions
  • severe lung inflammation causing respiratory failure (adult respiratory distress syndrome)
  • a skin rash like severe sunburn which can occur on skin that has previously been exposed to radiotherapy (radiation recall)
  • fluid in the lungs
  • scarring of the air sacs of the lung associated with radiation therapy (radiation toxicity)
  • gangrene of fingers or toes
  • inflammation of the blood vessels (peripheral vasculitis).

Very rare: may affect up to 1 in 10,000 users

  • increased platelet count
  • inflammation of the lining of the large bowel, caused by reduced blood supply (ischaemic colitis)
  • low haemoglobin level (anaemia), low white blood cells and low platelet count will be detected by a blood test
  • clots forming in small blood vessels (thrombotic microangiopathy).

Not known (cannot be estimated from the available data)

  • sepsis: when bacteria and their toxins circulate in the blood and start to damage the organs
  • skin redness with swelling (pseudocellulitis).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

  1. 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. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

After reconstitution:

Chemical and physical in-use stability has been demonstrated for 24 hours at 15-30°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 30°C.

The reconstituted solution should not be refrigerated.

Do not use this medicine if you notice a cloudy solution or an insoluble precipitate.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. Contents of the pack and other information

Available in 200mg and 1000mg.

  • The active substance is: gemcitabine
  • The other ingredients are: Mannitol USP, Sodium acetate USP, Sodium hydroxide USPNF, Hydrochloric acid USPNF.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

 

 

 

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