DBL™ Fluorouracil

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Fluorouracil 50 mg/mL;  ;  
Available from:
Pfizer New Zealand Limited
INN (International Name):
Fluorouracil 50 mg/mL
Dosage:
50 mg/mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Fluorouracil 50 mg/mL    
Units in package:
Vial, 5 x 5mL pack, 5 dose units
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Chemische Fabrik Berg GmbH
Therapeutic indications:
DBL® Fluorouracil Injection B.P. is indicated alone or in combination for the palliative treatment of malignant tumours, particularly of the breast, colon or rectum; and in the treatment of gastric, primary hepatic, pancreatic, uterine (cervical particularly), ovarian and bladder carcinomas. Fluorouracil should only be used when other proven measures have failed or are considered impractical.
Product summary:
Package - Contents - Shelf Life: Vial, 5mL - 5 dose units - 18 months from date of manufacture stored Store at 8-25°C, do not refrigerate. Protect from light - Vial, 10mL - 5 dose units - 24 months from date of manufacture stored Store at 8-25°C, do not refrigerate. Protect from light - Vial, glass, 50ml - 1 dose units - 24 months from date of manufacture stored Store at 8-25°C, do not refrigerate. Protect from light - Vial, glass, 20ml - 5 dose units - 24 months from date of manufacture stored Store at 8-25°C, do not refrigerate. Protect from light
Authorization number:
TT50-3755/1a
Authorization date:
1986-08-27

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NEW ZEALAND DATA SHEET

1. PRODUCT NAME

Fluorouracil 25 mg/ml Solution for injection.

Fluorouracil 50 mg/ml Solution for injection.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of DBL

Fluorouracil containing 25 mg or 50 mg of fluorouracil.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

DBL™ Fluorouracil Injection BP is a clear, colourless to slightly yellow solution.

Fluorouracil is a sterile preservative free solution of 5-Fluorouracil in Water for

Injection, prepared with the aid of Sodium Hydroxide.

The pH of the solution is approximately 8.9.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Fluorouracil Injection is indicated alone or in combination for the palliative

treatment of malignant tumours, particularly of the breast, colon or rectum; and in the

treatment of gastric, primary hepatic, pancreatic, uterine (cervical particularly), ovarian

and bladder carcinomas.

Fluorouracil

should

only

used

when

other

proven

measures

have

failed

considered impractical.

4.2 Dose and method of administration

Dose

The dosage being based on the patient's actual weight. Ideal weight is used only if the

patient is obese or if there has been a spurious weight gain due to oedema, ascites or other

forms of abnormal fluid retention.

The total daily dose of fluorouracil should not exceed 1 gram. The initial recommended

doses should be reduced by one third to a half if any of the following conditions are

present:

poor nutritional state

after major surgery (within previous 30 days)

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inadequate bone marrow function (W.B.C. count less than 5,000 per mm³; platelet

count less than 100,000 per mm

impaired hepatic and/or renal function.

The following regimes have been recommended for use of fluorouracil as a single agent

in adults:

Intravenous Infusion:

15 mg/kg bodyweight (to a maximum of 1 g daily) diluted in 300-500mL of 5% glucose

given over a period of 4 hours. The infusion may be repeated daily until the first

gastrointestinal side effects appear (stomatitis, diarrhoea, leucopenia, thrombocytopenia).

Treatment must be discontinued until the side effects have receded (until the W.B.C.

count has risen to 3,000 - 4,000 per mm³ and the platelet count to 80,000 - 100,000 per

). The patient may then be placed on a maintenance therapy programme.

Intravenous Injection:

12 mg/kg bodyweight daily for 3 consecutive days.

Providing there are no signs of toxic effects, the patient may then be given 6mg/kg I.V.

on the 5

and 9

days.

If after the 9

day there is still no sign of toxicity, the patient may be placed on

maintenance

therapy.

instances

toxic

side

effects

must

disappear

before

maintenance therapy is started.

Maintenance Therapy:

5 - 10 mg/kg bodyweight by I.V. injection once a week. Toxic symptoms seldom occur

during maintenance therapy. If, however, they do appear, therapy must be discontinued

until the symptoms regress.

Methods of Administration

Fluorouracil

Injection

administered

intravenous

infusion

intravenous injection.

Fluorouracil may be used in combination with other cytostatic agents or radiotherapy. In

such cases doses should be correspondingly reduced. DBL

Fluorouracil Injection may

also be administered as a 24 hour intra-arterial continuous drip infusion (5 - 7. mg/kg

bodyweight daily).

4.3 Contraindications

Fluorouracil is contraindicated in patients who are debilitated, who are suffering from

bone marrow depression following radiotherapy or therapy with other antineoplastic

agents, and in patients who are pregnant.

Fluorouracil must not be taken within 4 weeks of treatment with brivudine, sorivudine or

their chemically related analogues. Brivudine, sorivudine and their analogues are potent

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inhibitors

enzyme

dihydropyrimidine

dehydrogenase

(DPD),

which

degrades

fluorouracil (see Section 4.5).

4.4 Special warnings and precautions for use

It is recommended that fluorouracil be given only by or under strict supervision of a

qualified physician who is well acquainted with the use of potent antimetabolites.

Because of the possibility of severe toxic reactions, all patients should be hospitalised, at

least during the initial course of therapy.

Fluorouracil should not be re-administered after a documented cardiovascular reaction

(arrhythmia, angina, ST segment changes) as there is a risk of sudden death.

Any form of therapy which adds to the stress of the patient, interferes with nutritional

uptake or depresses bone marrow function, will increase the toxicity of fluorouracil.

Adequate treatment with fluorouracil is usually followed by leucopenia, the lowest white

blood cell (W.B.C.) count commonly being observed between the 9

and 14

day of the

first course, but occasionally being delayed for as long as 20 days. The count usually

returns to normal by the 30

day. Daily monitoring of platelets and W.B.C. counts are

recommended and treatment should be stopped if platelets fall below 100,000 per mm³ or

the W.B.C. count falls below 3,500 per mm³. If the W.B.C. count falls below 2,000 per

mm³, it is recommended that the patient be placed in protective isolation in the hospital

and given the appropriate preventative treatment for systemic infection.

Treatment should also be discontinued at the first sign of oral ulceration or if there is

evidence of gastrointestinal side effects such as stomatitis, diarrhoea or bleeding from the

G.I. tract.

Patients taking phenytoin concomitantly with fluorouracil should undergo regular testing

because of the possibility of an elevated plasma level of phenytoin (see section 4.5).

Toxicity

Fluorouracil has a narrow margin of safety and is a highly toxic drug. Fluorouracil

therapy should be discontinued promptly whenever one of the following signs of toxicity

appears:

leucopenia,

thrombocytopenia,

stomatitis,

oesophagopharyngitis,

intractable

vomiting, diarrhoea, melena haemorrhage, oral ulceration, evidence of gastrointestinal

ulceration or bleeding. The ratio between effective and toxic dose is small and therapeutic

response is unlikely without some degree of toxicity. Care must be taken, therefore, in the

selection of patients and adjustment of dosage.

Fluorouracil should be used with caution in patients with reduced renal or liver function

or jaundice.

Myelosupression

Cytotoxic agents, including fluorouracil, may produce myelosuppression (including, but

limited

leucopenia,

granulocytopenia,

pancytopenia

thrombocytopenia).

Leucopenia and thrombocytopenia commonly follow treatment with fluorouracil.

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Clinical consequences of sever myelosuppression include infections. Viral, bacterial, fungal

and/or parasitic infections, either localized or systemic, may be associated with the use of

fluorouracil alone or in combination with other immunosuppressive agents. These infections

may be mild, but can be severe and at times fatal.

Cardiotoxicity

There is an increased risk of death associated with re-administration of fluorouracil in

patients with a documented cardiovascular reaction (See section 4.8).

Angina,

abnormalities

myocardial

infarction

have

been

reported

after

administration of fluorouracil. Attention should therefore be paid to patients who experience

chest pain during treatment, and patients with a history of heart disease.

Renal and hepatic impairment

Fluorouracil should be used with caution in patients with renal and/or hepatic dysfunction.

Dihydropyrimidine dehydrogenase deficiency

Rarely,

severe

toxicity

(e.g.,

stomatitis,

diarrhoea,

neutropenia,

neurotoxicity)

associated

with fluorouracil has been

attributed to deficiency

of dihydropyrimidine

dehydrogenase (DPD) activity. Fatal outcome has been reported in some cases. Absence

of this catabolic enzyme appears to result in prolonged clearance of fluorouracil. Special

attention

should

given

status

when

evaluating

patients

experiencing

fluorouracil-related toxicities.

Combination chemotherapy/radiotherapy

May depress bone marrow function and increase the toxicity of fluorouracil. Extreme

caution is necessary when administering fluorouracil to patients who have had high dose

pelvic irradiation, or have been previously treated with alkylating agents. Fluorouracil

treatment

potentiate

necrosis

caused

radiation.

Concomitant

other

chemotherapeutic agents may depress bone marrow function and increase the toxicity of

fluorouracil.

Photosensitivity reactions

Some

patients

experience

photosensitivity

reactions

following

administration

fluorouracil, it is recommended that patients are warned to avoid prolonged exposure to

sunlight (see section 4.8).

Immunosuppressant effects/increased susceptibility to infections

Administration of live or live-attenuated vaccines in patients immunocompromised by

chemotherapeutic agents including fluorouracil, may result in serious or fatal infections.

Vaccination with a live vaccine should be avoided in patients receiving fluorouracil. Killed

or inactivated vaccines may be administered; however, the response to such vaccines may be

diminished.

Hand-foot syndrome.

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The administration of fluorouracil has been associated with the occurrence of palmar-

plantar erythrodysesthesia syndrome, also known as hand-foot syndrome. Continuous-

infusion

fluorouracil

increase

incidence

severity

palmar-plantar

erythrodysesthesia. This syndrome has been characterized as a tingling sensation of hands

and feet, which may progress over the next few days to pain when holding objects or

walking. The palms and soles become symmetrically swollen and erythematous with

tenderness of the distal phalanges, possibly accompanied by desquamation. Interruption

of therapy is followed by gradual resolution over 5 to 7 days. Supplementation of

chemotherapy

with

oral

pyridoxine

been

reported

prevent

resolve

such

symptoms.

Effects on laboratory tests

Fluorouracil could interfere with diagnostic tests of thyroid function by causing rises in total

thyroxine and liothyronine due to increased globulin binding. Plasma albumin may be

decreased because of drug-induced protein malabsorption.

Use in elderly

Fluorouracil should be used with caution in elderly patients. Aged 70 years or older and

female

gender

reported

independent

risk

factors

severe

toxicity

from

fluorouracil based chemotherapy. Close monitoring for multiple organ toxicities and

vigorous supportive care of those with toxicity are necessary.

4.5 Interaction with other medicines and other forms of interaction

Cytotoxic agents

: All myelosuppressive drugs (e.g., Cytotoxic agents used in combination

chemotherapy) can increase hematotoxicity of fluorouracil.

Folinic

acid

(Leucovorin)

enhances

DNA-directed

toxicity

fluorouracil.

This

combination should be used with caution as it is reported to increase the gastrointestinal

toxicity of fluorouracil.

Allopurinol

decrease

degree

bone

marrow

depression

produced

fluorouracil. Studies of this possibility have reported conflicting results.

Various agents have been reported to biochemically modulate the antitumour efficacy or

toxicity of fluorouracil. Common drugs include methotrexate, metronidazole, leucovorin.

Pretreatment with cimetidine prior to IV fluorouracil increased the AUC by 27%. The

total body clearance was reduced by 28%.

Increased phenytoin plasma concentrations have been reported during concomitant use of

phenytoin with capecitabine or its metabolite fluorouracil. Formal interaction studies

between phenytoin and capecitabine have not been conducted, but the mechanism of

interaction is presumed to be inhibition of CYP2C9 isoenzyme system by capecitabine.

Serum

levels

phenytoin

sustained

above

optimal

range

produce

encephalopathy,

confusional

states

(delerium

psychosis),

rarely

irreversible

cerebellar

dysfunction.

Therefore,

patients

taking

phenytoin

concomitantly

with

capecitabine or fluorouracil should be regularly monitored for increased phenytoin levels

(see section 4.4).

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Brivudine and sorivudine.

Brivudine, sorivudine or their chemically related analogues

irreversibly inhibit DPD, resulting in a significant increase in fluorouracil exposure. This

may lead to increased fluoropyrimidine-related toxicities with potentially fatal outcome.

Therefore, either a different antiviral therapy may be used or there should be an interval

of at least 4 weeks between the administration of brivudine, sorivudine, or the analogues

and the start of fluorouracil treatment (see Section 4.3). In the case of accidental

administration of nucleoside analogues that inhibit DPD activity to patients treated with

fluorouracil,

effective

measures

should

taken

reduce

fluorouracil

toxicity.

Immediate hospitalization is recommended.

Radiation therapy

. Radiation therapy on the bone marrow, especially to the area of the

chest and mediastinum, may potentiate the bone marrow effects of fluorouracil.

Warfarin

Elevated

levels

and occasional

episodes

bleeding

have

been

reported during concomitant use of warfarin and fluorouracil or its analogues. In these

cases, fluorouracil has usually been administered as one component of an antineoplastic

combination

regimen.

Adequate

anticoagulant

response

warfarin

other

coumarin-derivative therapy should be monitored regularly in patients taking fluorouracil.

Laboratory values.

Fluorouracil treatment may interfere with some laboratory tests.

Increases in total serum thyroxine concentration (due to increased binding to globulin)

have been reported.

4.6 Fertility, pregnancy and lactation

Fertility

Fluorouracil has not been adequately studied in animals to permit an evaluation of its

effects on fertility and general reproductive performance. However, doses of 125 or

250mg/kg, administered intraperitoneally, have been shown to induce chromosomal

aberrations and changes in chromosomal organisation of spermatogonia in rats.

Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient

infertility. However, in studies with a strain of mouse which is sensitive to the induction

of sperm head abnormalities after exposure to a

range of chemical mutagens

carcinogens, fluorouracil did not produce any abnormalities at oral doses of up to

80mg/kg/day. In female rats, fluorouracil, administered intraperitoneally at weekly doses

50mg/kg

three

weeks

during

pre-ovulatory

phase

oogenesis,

significantly reduced the incidence of fertile matings, delayed the development of pre-

and post-implantation embryos, increased the incidence of pre-implantation lethality and

induced chromosomal anomalies in these embryos. In a limited study in rabbits, a single

25mg/kg dose of fluorouracil or 5 daily doses of 5mg/kg had no effect on ovulation,

appeared not to affect implantation and had only a limited effect in producing zygote

destruction. Compounds such as fluorouracil, which interfere with DNA, RNA and

protein synthesis, might be expected to have adverse effects on gametogenesis.

In general, use of a contraceptive is recommended during cytotoxic drug therapy.

Pregnancy - Category D

This category specifies drugs which have caused an increased incidence of human fetal

malformations

irreversible

damage.

These

drugs

also

have

adverse

pharmacological effects.

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Safety for use in pregnancy has not been established. Fluorouracil should only be used in

women of child bearing potential if the expected benefits outweigh the risks of therapy, and

adequate contraception is used. If the patient becomes pregnant whilst receiving the drug she

should be advised of the potential hazards on the fetus. Men undergoing fluorouracil

treatment should also ensure they use effective contraceptive measures.

Fluorouracil is therefore strictly contraindicated in pregnancy.

Breast-feeding

It is not known whether fluorouracil is excreted in breast milk. To avoid possible harmful

effects in the infant, breast-feeding is not advised during fluorouracil therapy.

4.7 Effects on ability to drive and use machines

The effect of fluorouracil on the ability to drive and use machinery has not been

systematically evaluated.

4.8 Undesirable effects

The ratio between effective and toxic dose is small and therapy with fluorouracil is

usually accompanied by some degree of adverse effects. Patients should be carefully

observed and dosage adjustment may have to be made. Deaths have been reported.

Infections and Infestations

Septic shock, sepsis, neutropenic sepsis, pneumonia, superinfection, urinary tract infection,

catheter related infection, cellulitis, pharyngitis and other infections.

Blood and lymphatic system disorders

Leucopenia, primarily granulocytopenia commonly occurs. The nadir for white blood cell

count usually occurs from the 9

to the 14

day after initiation of therapy, but may occur

late

day.

count

usually

returns

normal

day.

Thrombocytopenia may also occur, with the lowest platelet counts occurring from the 7

the 17

day of therapy.

Nervous system disorders

Neurological:

Combination therapy with 5-fluorouracil and levamisole has been associated

with

leukoencephalopathy

multifocal

inflammatory

leukoencephalopathy

(MILE).

Symptoms may include memory loss, confusion, paraesthesia, lethargy, muscle weakness,

speech

disturbances,

coma

seizures.

cerebrospinal

fluid

show

mild

pleiocytosis, and computed tomography and magnetic resonance scans may show lesions in

the white matter suggestive of demyelination. If this syndrome occurs, treatment should be

discontinued immediately. The condition is at least partially reversible if 5-fluorouracil and

levamisole are discontinued and corticosteroids given.

Neurotoxicity:

Disorientation, confusion, euphoria, ataxia, nystagmus, headache, slurred

speech, dizziness, unsteadiness and acute cerebellar syndrome have occurred in patients

receiving fluorouracil. These symptoms may persist after therapy is discontinued.

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Eye disorders

Systemic fluorouracil treatment has been associated with various types of ocular toxicity.

Additionally several other reports have been noted including excessive lacrimation,

dacryostenosis, visual changes and photophobia.

Cardiac disorders

There have been reports of myocardial infarction*, angina pectoris*, cardiac shock*,

cardiac failure*, cardiomyopathy*, myocarditis*, pericarditis*, chest pain, tachycardia,

breathlessness, arrhythmia and E.C.G. changes (ST segment changes) after administration

of fluorouracil. There have been reports of sudden death in patients readministered

fluorouracil after a documented cardiovascular reaction.

Gastrointestinal disorders

The most pronounced dose-limiting toxic effects of fluorouracil are on the normal,

rapidly proliferating tissues of the bone marrow and the lining of the gastrointestinal tract.

Diarrhoea, nausea and vomiting are seen commonly during therapy and may be treated

symptomatically. Nausea and vomiting may be controlled with an appropriate antiemetic.

Other

reported

gastrointestinal

symptoms

diarrhoea,

proctitis,

melaena

oesophagitis, therefore the dose may require adjustment or therapy may need to be

discontinued. Gastrointestinal side effects may be exacerbated if fluorouracil is given

with folinic acid (leucovorin).

Skin and subcutaneous tissue disorders

Alopecia may be seen in a substantial number of cases, but is reversible. Dermatitis,

hyperpigmentation, changes in the nail beds and ataxia have been reported. Skin rashes

have

been

associated

with

fluorouracil

therapy.

Palmar-Palmar

Erythrodysesthesia

Syndrome,

thrombophlebitis

asymptomatic

hyperpigmentation

over

vascular

channels have also been reported. Continuous-infusion fluorouracil may increase incidence

and severity of palmar-plantar erythrodysesthesia. Photosensitivity reaction.

Other

Local injection site reaction. Fevers have also been reported. Rarely, anaphylaxis or

generalised allergic reactions have occurred in patients receiving fluorouracil. Pyrexia

and chest pain.

Listed cardiac disorders associated with 5-flouorouracil, may lead to cardiac arrest.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

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possibility

overdosage

with

fluorouracil

unlikely

view

mode

administration.

Symptoms

possibility

overdosage

with

fluorouracil

unlikely

view

mode

administration. High dosages or prolonged treatment with fluorouracil can result in life-

threatening

intoxication

symptoms;

anticipated

manifestations

would

nausea,

vomiting, diarrhoea, gastrointestinal ulcers and hemorrhage and myelosuppression (include

thrombocytopenia, leucopenia and granulocytopenia).

Treatment

Uridine triacetate is a specific antidote for the treatment of 5-fluorouracil overdose or the

treatment of severe early-onset toxicities. It should be administered within 96 hours after end

of 5-fluorouracil infusion. In the event uridine triacetate is not available, treatment is

symptomatic and supportive. Patients who have been exposed to an overdose of fluorouracil

should be monitored haematologically for at least 4 weeks. Should abnormalities appear,

appropriate therapy should be utilised.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Fluorouracil is an analogue of uracil, a component of ribonucleic acid. The drug is

believed to function as an antimetabolite. After intracellular conversion to the active

deoxynucleotide, it interferes with the synthesis of DNA by blocking the conversion of

deoxyuridylic acid to thymidylic acid by the cellular enzyme thymidylate synthetase.

Fluorouracil may also interfere with RNA synthesis.

5.2 Pharmacokinetic properties

After intravenous administration, fluorouracil is distributed through the body water and

disappears from the blood within 4 hours. It is preferentially taken up by actively dividing

tissues and tumours after conversion to its nucleotide. Fluorouracil readily enters the

C.S.F.

About 20% is excreted unchanged in the urine and the remainder is mostly metabolised in

the liver by the usual body mechanisms for uracil.

5.3 Preclinical safety data

Carcinogenicity

Long term studies in animals to evaluate the carcinogenic potential of fluorouracil have

not been conducted. However, there was no evidence of carcinogenicity in small groups

of rats given fluorouracil orally at doses of 0.01, 0.3, 1 or 3 mg per rat 5 days per week

for 52 weeks, followed by a 6 month observation period. On the basis of the available

data, no evaluation can be made of the carcinogenic risk of fluorouracil to humans.

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Genotoxicity

Oncogenic transformation of fibroblasts from mouse embryo has been induced

in vitro

fluorouracil, but the relationship between oncogenicity and mutagenicity is not clear. A

positive effect was observed in the micronucleus test on bone marrow cells of the mouse,

and fluorouracil at very high concentrations produced chromosomal breaks in hamster

fibroblasts

in vitro

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydroxide

Water for injection

6.2 Incompatibilities

Admixture with acidic drugs or drugs that decompose in an alkaline environment should

be avoided. Fluorouracil is reported to be incompatible with cytarabine, diazepam,

methotrexate, platinum compounds, doxorubicin (and presumably other anthracyclines

that are unstable at alkaline pH), and calcium folinate (leucovorin) or levoleucovorin

calcium.

6.3 Shelf life

24 months

18 months (only for 250 mg/5 mL)

6.4 Special precautions for storage

Store at 8 - 25°C. Do not refrigerate. Protect from light.

6.5 Nature and contents of container

DBL™ Fluorouracil Injection BP is available in clear glass vials containing 25 mg/mL or 50

mg/mL of fluorouracil in the following presentations and pack sizes.

Strength

Packs

500 mg/20 mL

10 x 20mL vials

250 mg/5 mL

5 x 5mL vials

2.5 g/100 mL

1 x 100mL vial

500 mg/10 mL

5 x 10mL vials

1 g/20 mL

5 x 20mL vials

2.5 g/50 mL

1 x 50mL vial

250 mg/10 mL

5 x 10 mL vials

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