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

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

Recommended posology:
Bladder cancer
Combination use
The recommended dose for Gemcitabine is 1,000 mg/m2, given by 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 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 1,000 mg/m2, given by 30 minute intravenous infusion.
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 1,000 mg/m2, given by 30 minute intravenous infusion.
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 1,250 mg/m2 body surface area given as a 30 minute
intravenous infusion on Days 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 infusion, followed by Gemcitabine (1,250 mg/m2) as a 30 minute intravenous infusion 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 1,000 mg/m2
administered on Days 1 and 8 of each 21 day cycle as a 30 minute intravenous infusion. 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 (x106/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:

*Treatment omitted will not be reinstated within a cycle before the absolute granulocyte count
reaches at least 500 (10⁶/l) and the platelet count reaches 50,000 (10⁶/l).

*Treatment omitted 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 1,500 (x10⁶/l) and the platelet count
reaches 100,000 (x10⁶/l).

*Treatment omitted 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 1,500 (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 neutropenia
• Platelets < 25,000 x 106 /l
• Cycle delay of more than 1 week due to toxicity

Method of administration
Citabol 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 renal or hepatic impairment
Citabol should be used with caution in patients with hepatic or renal insufficiency 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)
Citabol 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)
Citabol is not recommended for use in children under 18 years of age due to insufficient data on
safety and efficacy.

Hypersensitivity to the active substance or to any of the excipients. Breast-feeding (see section 4.6).

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

Haematological toxicity
Citabol can suppress bone marrow function as manifested by leucopenia, thrombocytopenia and anaemia.
Patients receiving Citabol should be monitored prior to each dose for platelet, leucocyte and
granulocyte counts. Suspension or modification of therapy should be considered when druginduced
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 Citabol 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 Citabol treatment is given together with other chemotherapy.

Hepatic and renal insufficiency
Administration of Citabol 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
insufficiency.
Laboratory evaluation of renal and hepatic function (including virological tests) should be
performed periodically.
Citabol should be used with caution in patients with hepatic insufficiency or with impaired renal
function as there is insufficient information from clinical studies to allow clear dose
recommendation for this patient population (see section 4.2).

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

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.

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

Cardiovascular
Due to the risk of cardiac and/or vascular disorders with Citabol, 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 Citabol therapy. If
such effects develop, consideration should be made to discontinuing Citabol 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 Citabol (see section 4.8). HUS is potentially lifethreatening
disorder. Citabol should be discontinued at the first signs of any evidence of
microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant
thrombocytopenia, 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, Citabol caused hypospermatogenesis in male mice (see section 5.3). Therefore,
men being treated with Citabol 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 Citabol (see section 4.6).

Sodium
Citabol powder for solution for infusion 1000 mg contains 17.5 mg (<1 mmol) sodium per vial.
This should be taken into consideration by patients on a controlled sodium diet.

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.

Fertility
In fertility studies, Citabol caused hypospermatogenesis in male mice (see section 5.3). Therefore,
men being treated with Citabol 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 Citabol (see section 4.6).

Pregnancy
There are no adequate data from the use of Citabol 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 Citabol is excreted in human milk, and adverse effects on the suckling child
cannot be excluded. Breast-feeding must be discontinued during Citabol therapy.

No studies on the effects on the ability to drive and use machines have been performed. However,
Citabol 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.

The most commonly reported adverse drug reactions associated with Citabol 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% of 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, 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).
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
Blood and lymphatic system disorders	Very Common Leucopenia (Neutropenia 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). Thrombocytopenia Anaemia Common Febrile neutropenia Very Rare Thrombocytosis
Immune system disorders	Very Rare Anaphylactoid reaction
Metabolism and nutrition disorders	Common Anorexia
Nervous system disorders	Common Headache Insomnia Drowsiness Uncommon: Cerebrovascular accident Very Rare: Posterior Reversible Encephalopathy Syndrome (see section 4.4)
Cardiac disorders	Uncommon: Arrythmias, 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)
Gastro-intestinal disorders	Very Common Vomiting Nausea Common Diarrhoea Stomatitis and ulceration of the mouth Constipation Very Rare: Ischaemic colitis
Hepato-biliary 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
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 neutropenia, increases when
Citabol 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 neutropenia occur more frequently when Citabol is used in combination with
paclitaxel. Fatigue, which is not associated with anaemia, usually resolves after the first cycle.

*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

Combination use in ovarian cancer

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

Reporting to National Regulatory Authority
To report any side effects
Saudi Arabia
The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Ext: 2317-2356-2353-2354-2334-2340
• Toll free phone: 8002490000
• E.mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc

There is no known antidote for overdose of Citabol . Doses as high as 5,700 mg/m² have been
administered by intravenous infusion 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.

Pharmacotherapeutic group: Pyrimidine analogues. ATC code: L01BC05

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.

Anti-tumoural activity in preclinical models
In animal tumour models, anti-tumoural 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 anti-tumoural 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 (logrank 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).

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
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 infusion 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 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'-deoxy2',- 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 (interindividual
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 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 infusion, 1,000 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.

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 perinatal and
postnatal development.

Citabol 200mg powder for solution for infusion contains:
Mannitol
Sodium acetate
Hydrochloric acid(for pH adjustment)
Sodium hydroxide (for pH adjustment)

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

Unopened vials : 2 years. Reconstituted solution: 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, inuse storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at room temperature, unless reconstitution (and further dilution, if applicable) has taken place in controlled and validated aseptic conditions. Solutions of reconstituted Citabol should not be refrigerated, as crystallization may occur.

Unopened vial: Store below 30°C.
For storage conditions of the reconstituted medicinal product, see section 6.3.

Type I clear glass vials, stoppered with a gray butyl slotted rubber stopper and sealed with an aluminium sealand tampered with flip-off top.
Each pack contains 1 vial.

Handling
The normal safety precautions for cytostatic agents must be observed when preparing and disposing
of the infusion solution. Handling of the solution for infusion should be done in a safety box and
protective coats and gloves should be used. If no safety box is available, the equipment should be
supplemented with a mask and protective glasses.
If the preparation comes into contact with the eyes, this may cause serious irritation. The eyes
should be rinsed immediately and thoroughly with water. If there is lasting irritation, a doctor
should be consulted. If the solution is spilled on the skin, rinse thoroughly with water.
 

Instructions for reconstitution (and further dilution, if performed)
The only approved diluent for reconstitution of Citabol sterile powder is sodium chloride 9 mg/ml
(0.9%) solution for injection (without preservative). Due to solubility considerations, the maximum
concentration for Gemcitabine upon reconstitution is 40 mg/ml. Reconstitution at concentrations
greater than 40 mg/ml may result in incomplete dissolution and should be avoided.

1. Use aseptic technique during the reconstitution and any further dilution of Citabol for intravenous
infusion administration.

2. To reconstitute, add 5 ml of sterile sodium chloride 9 mg/ml (0.9 %) solution for injection,
without preservative, to the 200 mg vial. The total volume after reconstitution is 5.26 ml. This
yields a Gemcitabine concentration of 38 mg/ml, which includes accounting for the displacement
volume of the lyophilised powder. Shake to dissolve. Further dilution with sterile sodium chloride 9
mg/ml (0.9 %) solution for injection, without preservative, can be done. Reconstituted solution is a
clear solution.

3. Parenteral medicinal products should be inspected visually for particulate matter and
discoloration prior to administration. If particulate matter is observed, do not administer.

Any unused product or waste material should be disposed of in accordance with local requirements.