Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
Proposed Professional Information  
SCHEDULING STATUS  
S4  
1 NAME OF THE MEDICINE  
CERBIGEM 200 (lyophilised powder for solution for infusion)  
CERBIGEM 1 (lyophilised powder for solution for infusion)  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine.  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine.  
For full list of excipients, see section 6.1.  
CERBIGEM 200 contains 200 mg mannitol.  
CERBIGEM 1 contains 1000 mg mannitol.  
3 PHARMACEUTICAL FORM  
White to off white lyophilised powder for solution for infusion.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
•
CERBIGEM is indicated for the treatment of patients  
with locally advanced or metastatic non-small cell lung  
cancer.  
•
CERBIGEM is indicated as first-line treatment for  
patients with locally advanced (non-resectable Stage  
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Page 1 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
II or Stage Ill) or metastatic (Stage IV)  
adenocarcinoma of the pancreas. CERBIGEM is  
indicated for patients previously treated with 5-FU.  
•
•
CERBIGEM is indicated for treatment of patients with  
transitional cell bladder cancer.  
CERBIGEM, 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.  
•
CERBIGEM, alone or in combination, is indicated for  
the treatment of patients with recurrent epithelial  
ovarian carcinoma who have relapsed following  
platinum-based chemotherapy.  
4.2 Posology and method of administration  
CERBIGEM is for intravenous use only.  
Posology  
Non-small cell lung cancer:  
Adults: The recommended monochemotherapy dosage is  
1 000 mg/m2, given by 30 minute intravenous infusion. This  
should be repeated once weekly for three weeks, followed by  
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Page 2 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
a one week rest period. This four week cycle is then repeated.  
Dosage reduction is applied based upon the amount of toxicity  
experienced by the patient.  
CERBIGEM may be used in combination with cisplatin using  
either a three week or a four week schedule. One of the  
following regimens is suggested:  
3 week schedule: CERBIGEM 1 250 mg/m2, given by 30  
minute intravenous infusion on days 1 and 8 of every 21 day  
cycle and cisplatin 100 mg/m2 on day 1. Dosage reduction  
with each cycle or within a cycle may be applied based upon  
the amount of toxicity experienced by the patient.  
4 week schedule: CERBIGEM 1 000 mg/m2 on days 1, 8 and  
15 of every 28 day cycle and cisplatin 100 mg/m2 on either  
day 1, 2 or 15 of therapy. Dose 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 CERBIGEM 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  
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Page 3 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
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 amount of toxicity experienced by the  
patient.  
Bladder cancer:  
Adults: The recommended monochemotherapy dosage of  
CERBIGEM is 1 250 mg/m2, given by 30 minute intravenous  
infusion. The dose should be given on days 1, 8 and 15 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.  
CERBIGEM may be used in combination with cisplatin. The  
recommended dose of CERBIGEM is 1 000 mg/m2, given by  
30 minute intravenous 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 CERBIGEM 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.  
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Page 4 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
A clinical trial showed more myelosuppression when cisplatin  
was used in doses of 100 mg/m2  
Breast cancer:  
Adults: CERBIGEM 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 CERBIGEM (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 amount 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 CERBIGEM +  
paclitaxel combination.  
Ovarian Cancer:  
Single medicine use:  
Adults: The recommended dose of CERBIGEM is 800 to 1  
250 mg/m2, given by a 30 minute intravenous infusion. The  
dose should be given on days 1, 8 and 15 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.  
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Page 5 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
Combination use:  
Adults: CERBIGEM in combination with carboplatin is  
recommended using CERBIGEM 1 000 mg/m2 administered  
on days 1 and 8 of each 21 day cycle as a 30 minute  
intravenous infusion. After CERBIGEM, carboplatin will be  
given on day 1 consistent with a target AUC of 4,0 g/ml/min.  
Dosage reduction with each cycle or within a cycle may be  
applied based upon the amount of toxicity experienced by the  
patient.  
Patients receiving CERBIGEM should be monitored prior to  
each dose for platelet, leucocyte and granulocyte counts and,  
if necessary, the dose of CERBIGEM may be either reduced  
or withheld in the presence of haematological toxicity,  
according to the following scale:  
Absolute  
Platelet  
count  
% of full  
dose  
granulocyte  
count (× 106/ L)  
> 1 000  
(× 106/ L)  
> 100 000  
50 000 –  
100 000  
< 50 000  
and  
or  
100  
75  
500 – 1 000  
< 500  
or  
hold  
Periodic physical examination, and checks of renal and hepatic  
function should be made to detect non-haematologic toxicity.  
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Page 6 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
Dosage reduction with each cycle or within a cycle may be  
applied based upon the amount of toxicity experienced by the  
patient. Doses should be withheld until toxicity has resolved in  
the opinion of the medical practitioner.  
CERBIGEM is well tolerated during the infusion, with only a  
few cases of injection site reaction reported. CERBIGEM can  
be easily administered on an outpatient basis.  
Special populations:  
Patients with hepatic or renal impairment:  
CERBIGEM should be used with caution in patients with  
hepatic insufficiency or with impaired renal function as no  
studies have been done in patients with significant renal or  
hepatic impairment. There is insufficient information from  
clinical studies to allow clear dose recommendation for this  
patient population.  
Elderly patients: CERBIGEM has been well tolerated in  
patients over the age of 65. There is no evidence to suggest  
that dose adjustments are necessary in the elderly, although  
gemcitabine clearance and half-life are affected by age. (See  
Section 5.2)  
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Page 7 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
Paediatric population:  
Safety and efficacy in children have not been established. (See  
Section 4.3).  
Method of administration:  
CERBIGEM is for intravenous use only.  
Instructions for reconstitution: The only approved diluent for  
reconstitution of CERBIGEM is 0,9 % Sodium Chloride  
Injection without preservatives. It is not recommended that  
CERBIGEM be mixed with other medicines when  
reconstituted. Due to solubility considerations, the maximum  
concentration for CERBIGEM upon reconstitution is 40 mg/ml.  
Reconstitution at concentrations greater than 40 mg/ml may  
result in incomplete dissolution and should be avoided.  
To reconstitute, add at least 5 ml of 0,9 % Sodium Chloride  
Injection without preservatives to the 200 mg vial or at least 25  
ml of 0,9 % Sodium Chloride injection without preservatives to  
the 1 g vial. Shake to dissolve. The appropriate amount of  
medicine may be administered as prepared or further diluted  
with 0,9 % Sodium Chloride injection without preservatives.  
4.3 Contraindications  
•
Hypersensitivity to any of the ingredients of  
gemcitabine hydrochloride, or any of the  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
ingredients of CERBIGEM including the excipients.  
•
•
Pregnancy and lactation: The safety of  
CERBIGEM in human pregnancy and lactation has  
not been established (see Section 4.6).  
Use in children: Safety and efficacy in children have  
not been established.  
4.4 Special warnings and precautions for use  
Prolongation of the infusion time and increased dosing  
frequency have been shown to increase toxicity.  
CERBIGEM can suppress bone marrow function as  
manifested by leucopenia, thrombocytopenia and anaemia.  
Myelosuppression is usually mild to moderate and is more  
pronounced for the granulocyte count (see Section 4.2 and 4.8  
Blood and the lymphatic system disorders”).  
General: Patients receiving therapy with CERBIGEM must be  
monitored closely. Laboratory facilities should be available to  
monitor patient status. (See Section 4.2) for evaluation  
of renal and hepatic function. Treatment for a patient  
compromised by medicine toxicity may be required.  
Laboratory tests: Therapy should be started cautiously in  
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Page 9 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
patients with compromised bone marrow function. As with  
other oncolytics, the possibility of cumulative bone marrow  
suppression when using combination or sequential  
chemotherapy should be considered.  
Guidelines regarding dose modifications when medicine-  
induced marrow depression is detected are provided (see  
Section 4.2 ). Peripheral blood counts may continue to fall after  
the medicine is stopped.  
Renal toxicity: Renal failure and HUS (haemolytic-uraemic  
syndrome) have been reported rarely. CERBIGEM should be  
administered with caution to patients with impaired renal  
function. CERBIGEM should be discontinued at the first signs  
of microangiopathic haemolytic anaemia such as rapidly falling  
haemoglobin with concomitant thrombocytopenia, elevation of  
serum bilirubin, serum creatinine, blood urea nitrogen, or LDH  
(Lactate dehydrogenase). Renal failure may not be reversible  
even with discontinuation of therapy and dialysis may be  
required.  
Pulmonary toxicity: Interstitial pneumonitis together with  
pulmonary infiltrates has been seen in less than 1 % of  
patients. In such cases, CERBIGEM treatment must be  
stopped. Steroids may relieve the symptoms in such situations.  
Aug 2022  
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Page 10 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
Severe, rarely fatal pulmonary effects, such as pulmonary  
oedema, interstitial pneumonitis and ARDS (Acute (or Adult)  
respiratory distress syndrome) have been reported as less  
common or rare. In such cases, cessation of CERBIGEM  
treatment is necessary. Starting supportive treatment at an  
early stage may improve the situation.  
Carcinogenesis and mutagenesis:  
Cytogenic damage, has been produced by CERBIGEM in an in  
vivo assay. CERBIGEM induced forward mutation in vitro in a  
mouse lymphoma assay. The carcinogenic potential of  
CERBIGEM has not been established.  
Patients with renal or hepatic impairment: CERBIGEM  
should be used with caution in patients with impaired renal  
function or hepatic insufficiency. No studies have been done in  
patients with significant renal or hepatic impairment. Mild to  
moderate renal insufficiency (GFR from 30 ml/min to  
80 ml/min) has no consistent, significant effect on CERBIGEM  
pharmacokinetics.  
Administration of CERBIGEM 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  
Aug 2022  
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Page 11 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
Radiotherapy: Concurrent (given together or < 7 days apart):  
based on the results CERBIGEM has radiosensitizing activity.  
When CERBIGEM at a dose of 1 000 mg/m2 was administered  
concurrently for up to six 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. The  
optimum regimen for safe administration of CERBIGEM with  
therapeutic doses of radiation has not yet been determined  
(see Section 4.5)  
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 (CLS): Capillary leak syndrome has  
been reported in patients receiving gemcitabine as single  
medicine or in combination with chemotherapeutic medicines.  
The condition is usually treatable if recognised early and  
managed appropriately, but fatal cases have been reported.  
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Page 12 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
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.  
Posterior reversible encephalopathy syndrome (PRES):  
Reports of posterior reversible encephalopathy syndrome  
(PRES) with potentially severe consequences have been  
reported in patients receiving gemcitabine as single medicine or  
in combination with other chemotherapeutic medicines. 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  
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Page 13 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
therapy, if PRES develops during therapy.  
CERBIGEM contains mannitol and may have a mild laxative  
effect.  
4.5 Interaction with other medicines and other forms of  
interaction  
RADIOTHERAPY:  
CONCURRENT (GIVEN TOGETHER OR < 7 DAYS APART) –  
TOXICITY ASSOCIATED WITH THIS  
MULTIMODALITY THERAPY IS DEPENDENT ON MANY  
DIFFERENT FACTORS, INCLUDING DOSE OF CERBIGEM,  
FREQUENCY OF CERBIGEM ADMINISTRATION, DOSE OF  
RADIATION, RADIOTHERAPY PLANNING TECHNIQUE,  
THE TARGET TISSUE, AND TARGET VOLUME. BASED ON  
PRE-CLINICAL AND CLINICAL TRIAL RESULTS CERBIGEM  
HAS RADIOSENSITISING ACTIVITY.IN A SINGLE TRIAL,  
WHEN CERBIGEM 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 ESOPHAGITIS, AND  
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Page 14 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
PNEUMONITIS WAS OBSERVED, PARTICULARLY IN  
PATIENTS RECEIVING LARGE VOLUMES OF  
RADIOTHERAPY (MEDIAN TREATMENT VOLUMES 4 795  
cm3).  
THE OPTIMUM REGIMEN FOR SAFE ADMINISTRATION OF  
CERBIGEM WITH THERAPEUTIC DOSES OF RADIATION  
HAS NOT YET BEEN DETERMINED IN ALL TUMOUR  
TYPES.  
RADIATION INJURY HAS BEEN REPORTED ON  
TARGETED TISSUES (e.g. ESOPHAGITIS, COLITIS, AND  
PNEUMONITIS) IN ASSOCIATION WITH BOTH  
CONCURRENT AND NON-CONCURRENT USE OF  
CERBIGEM (see Section 4.4).  
Vaccines:  
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  
The safety of CERBIGEM in human pregnancy and lactation  
has not been established (see Section 4.3)  
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Page 15 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
The influence of CERBIGEM on fertility has not been  
established in humans.  
4.7 Effects on ability to drive and use machines  
CERBIGEM has been reported to cause mild to moderate  
somnolence. Patients should be cautioned against driving or  
operating machinery until it is established that they do not  
become somnolent.  
4.8 Undesirable effects  
a) Summary of the safety profile  
The most commonly reported adverse drug reactions  
associated with CERBIGEM 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 to 40 % of patients  
(highest incidence in lung cancer patients) and allergic skin  
rashes occurring in approximately 25 % of patients and  
associated with itching in 10 % of patients. The frequency and  
severity of adverse reactions are affected by the dose, infusion  
rate and intervals between doses (see Section 4.4).  
Dose-limiting adverse reactions are reductions in platelet,  
leucocyte and granulocyte counts (see Section 4.2).  
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Page 16 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
b) Tabulated summary of adverse reactions  
Infections and Infestations  
Less frequent  
Gangrene  
Blood and the lymphatic system disorders  
Frequent:  
Anaemia, leucopenia,  
thrombocytopenia,  
myelosuppression,  
microangiopathic haemolytic  
anaemia, febrile neutropenia  
Immune system disorders  
Less frequent:  
Anaphylactoid reaction (See  
Section 4.3)  
Metabolism and nutrition disorders  
Frequent:  
Anorexia  
Psychiatric disorders  
Frequent:  
Somnolence, insomnia  
Nervous system disorders  
Frequent:  
Headache, autonomic  
neuropathy  
Cardiac disorders  
Aug 2022  
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Page 17 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
Frequent:  
Dyspnoea  
Less frequent:  
Myocardial infarction,  
cardiac failure, dysrhythmia  
Vascular disorders  
Less frequent:  
Hypotension, peripheral  
vasculitis, ischemic colitis  
Frequency unknown:  
Respiratory, thoracic and mediastinal disorders  
Frequent:  
Influenza, cough, rhinitis  
Pulmonary oedema, adult  
respiratory distress  
Less frequent:  
syndrome (ARDS),  
bronchospasm, interstitial  
pneumonitis  
Gastrointestinal disorders  
Frequent:  
Nausea, vomiting, stomatitis  
Diarrhoea, constipation  
Less frequent:  
Skin and subcutaneous tissue disorders  
Frequent:  
Allergic skin rash, pruritus,  
alopecia  
Less frequent:  
Desquamation, scaling,  
vesiculation, ulceration,  
bullous skin eruptions  
Aug 2022  
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Page 18 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
Musculoskeletal and connective tissue disorders  
Frequent:  
Back pain, myalgia  
Renal and urinary disorders  
Frequent:  
Proteinuria, haematuria,  
Renal failure, haemolytic  
uraemic syndrome (HUS  
Less frequent:  
General disorders and administrative site conditions  
Frequent:  
Fever, asthenia, malaise,  
sweating, chills, oedema,  
peripheral oedema, facial  
oedema  
Investigations  
Frequent:  
Elevation of liver  
transaminases and alkaline  
phosphatase, increased  
gamma-glutamyl  
transferase, serum bilirubin  
increased, serum creatinine  
increased, blood urea  
nitrogen increased, LDH  
(lactate dehydrogenase)  
increase.  
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Page 19 of 30  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
Usually mild and  
non-progressive and rarely  
necessitating stopping of  
treatment.  
CERBIGEM should be used  
with caution in patients with  
impaired  
liver function (see Section  
4.4- Patients with renal or  
hepatic Impairment).  
Myelotoxicity has been  
reported to be modest even  
at high doses with  
gemcitabine.  
Oedema (including  
pulmonary oedema),  
hypotension and alopecia  
have also  
been reported. Gemcitabine  
may produce somnolence:  
patients so affected should  
not drive or operate  
machinery. Severe toxicity,  
in the form of potentially  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
life-threatening oesophagitis  
and pneumonitis has been  
seen in patients given  
radical radiotherapy to the  
thorax in association with  
gemcitabine. It should  
be used with caution in  
patients with impaired renal  
or hepatic function.  
Haemolytic-uraemic  
syndrome has been reported  
and led to irreversible renal  
failure; gemcitabine should  
be discontinued at the first  
signs of microangiopathic  
haemolytic anaemia.  
Less frequent:  
Increased gamma-glutamyl  
transferase and bilirubin  
Injury and poisoning  
Frequent:  
Radiosensitisation (see  
Sections 4.4 and 4.5)  
c) Description of selected adverse reactions  
The major dose limiting adverse effect of gemcitabine is bone-  
marrow depression, although this is reported to be modest and  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
rarely requires stopping therapy.  
d) Paediatric population  
CERBIGEM has not been studied in children and adolescents.  
Therefore, it should not be used in the paediatric age group  
until further data become available.  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of  
the medicine is important. lt allows continued monitoring of the  
benefit/risk balance of the medicine. Health care providers are  
asked to report any suspected adverse reactions via the "6.04  
Adverse Drug Reactions Reporting Form", found online  
under SAHPRA's publications:  
https://www.sahpra.org.za/publications/Index/8 or to the Holder  
of certificate of registration through the mail:  
pvg.cdma@heterogroups.com  
Post marketing experience  
Not Applicable  
4.9 Overdose  
There is no antidote for overdosage of CERBIGEM. ln the  
event of suspected overdose, the patient should be monitored  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
with appropriate blood counts and should receive supportive  
therapy, as necessary.  
5 PHARMACOLOGICAL ACTION  
5.1 Pharmacodynamic properties  
Category and class: A 26 Cytostatic agents  
Pharmacotherapeutic group: pyrimidine analogues ATC  
code:L01BC05  
Cellular metabolism and mechanism of action:  
Gemcitabine (dFdC) is metabolised intracellularly by  
nucleoside kinases to mono-, di- and triphosphates  
(dFdCMP, dFdCDP and dFdCTP) of which dFdCDP and  
dFdCTP are active. The cytotoxic action of gemcitabine  
appears to be due to inhibition of DNA synthesis by.  
two actions of dFdCDP and dFdCTP. Firstly, dFdCDP inhibits  
ribonucleotide reductase which is uniquely responsible for  
catalysing the reactions that generate the deoxynucleoside  
triphosphates for DNA synthesis. lnhibition of this enzyme by  
dFdCDP causes a reduction in the concentrations of  
deoxynucleosides in general, and especially in that of dCTP.  
Secondly, dFdCTP competes with dCTP for incorporation into  
DNA. 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  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
into DNA (self-potentiation). 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  
appears to induce the programmed cellular death process  
known as apoptosis  
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  
(Sphase) and under certain conditions blocking the  
progression of cells through the G1/S-phase boundary. ln vitro,  
the cytotoxic action of gemcitabine is both concentration and  
time dependent.  
Antitumour activity in pre-clinical models: ln animal tumour  
models, the antitumour activity of gemcitabine is schedule  
dependent. When administered daily, gemcitabine causes  
death in animals with minimal antitumour activity.  
However, when an every third or fourth day dosing schedule is  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
used, gemcitabine can be given at non-lethal doses that have  
excellent antitumour activity against a broad range of mouse  
tumours.  
5.2 Pharmacokinetic properties  
The pharmacokinetics of gemcitabine appear to be linear over  
the doses examined.  
Absorption:  
The following pharmacokinetic parameters were obtained for  
doses ranging from 500 to 2 592 mg/m2 that were infused over  
0,4 to 1,2 hours: Peak plasma concentrations (obtained  
within 5 minutes of end of the infusion):3,2 to 45,5 µg/mL  
Half-life: 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.  
Distribution:  
Volume of distribution of central compartment (VC): 12,4  
L/m2 for women and 17,5 L/m2 for men (inter-individual  
variability was 91,9 %).  
Volume of distribution of peripheral compartment (VP):  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
47,4 L/m2. The volume of peripheral compartment was not  
sensitive to gender.  
Plasma protein binding: negligible.  
Biotransformation  
Systemic clearance: 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 for women or the elderly should not  
necessitate a decrease in the gemcitabine dose (see Section  
4.2).  
Urinary excretion: less than 10 % is excreted unchanged.  
Mean renal clearance: 2 to 7 L/hr/m2.  
Systemic metabolism: Gemcitabine is rapidly metabolised by  
cytidine deaminase in the liver, kidney, blood and other  
tissues.  
The primary metabolite 2'-deoxy-2',2'-difluorouridine (dFdU) is  
not active and is found in plasma and urine. Formation of dFdU  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
from parent compound ranges from 91 % to 98 %. Tissue  
distribution of dFdU is extensive.  
Overall elimination: Amount recovered in one week following  
a single 30 minute infusion of 1 000 mg/m2 of radiolabelled  
gemcitabine: 92 % to 98 %, of which 99 % is urinary excretion  
of dFdU; 1 % of the dose is excreted in faeces.  
5.3 Preclinical safety data  
Not Applicable  
Environmental Risk Assessment  
Gemcitabine Hydrochloride is a well-established active  
ingredient used in pharmaceutical preparations for human use.  
Given the anticipated pattern of use and disposal of the  
product, the environmental exposure of the active substance  
and metabolites are expected to be very limited. The use of  
CERBIGEM is not considered warranting any environmental  
concerns or requiring any special product labelling.  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
Hydrochloric acid  
Mannitol  
Nitrogen  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
Sodium acetate trihydrate  
Sodium hydroxide  
Water for injection  
6.2 Incompatibilities  
In the absence of compatibility studies, this medicine must not  
be mixed with other medicines.  
6.3 Shelf life  
24 Months  
6.4 Special precautions for storage  
Before reconstitution  
Store at or below 25 °C, in a dry place, well closed in original  
vial, protected from light and moisture.  
KEEP OUT OF REACH OF CHILDREN.  
Keep the vial in the outer carton until required for use.  
After reconstitution:  
Solutions of CERBIGEM reconstituted with 0,9 % sodium  
chloride injection without preservatives should be stored below  
25 °C and should be administered within 24 hours.  
Discard unused portion. Do not refrigerate as crystallization may  
occur. Reconstituted CERBIGEM should be inspected visually  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
for particulate matter and discolouration, prior to administration.  
Procedures for proper handling and disposal of anti-cancer  
medicines should be considered.  
6.5 Nature and contents of container  
CERBIGEM 200  
10 ml tubular type 1 glass vials:  
Round clear tubular glass vials, type 1, with grey coloured  
rubber stopper and sealed with blue flip-off seals.  
CERBIGEM 1  
50 ml molded type 1 glass vials:  
Round clear molded glass vials, type 1, with grey coloured  
rubber stopper and sealed with blue flip-off seals.  
Each vial placed into an outer carton box together with a  
package insert.  
6.6 Special precautions for disposal and handling  
For reconstitution instructions, see Section 4.2.  
CERBIGEM is a cytotoxic medicine. Therefore, caution should  
be used during handling and preparation. Use of gloves and  
other protective clothing to prevent skin contact is  
recommended.  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: CERBIGEM 200 & CERBIGEM 1  
Dosage form and strength: Lyophilised powder for solution for infusion, 200 mg and 1 g  
Each 10 ml vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine  
Each 50 ml vial contains gemcitabine hydrochloride equivalent to 1 g gemcitabine  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate Campus, Building No.2,  
First Floor, 74 Waterfall drive,  
Midrand, 2066  
Telephone number: 012 644 1220  
e-mail address: nokuthula.n@heterodrugs.com  
8 REGISTRATION NUMBER(S)  
CERBIGEM 200: 52/26/0461  
CERBIGEM 1: 52/26/0462  
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE  
AUTHORISATION  
25 May 2021  
10 DATE OF REVISION OF THE TEXT  
06/10/2022  
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