DBL™ Sulfamethoxazole 400mg and Trimethoprin 80mg Concentrate injection BP

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Sulfamethoxazole 80 mg/mL;  ; Trimethoprim 16 mg/mL
Available from:
Pfizer New Zealand Limited
INN (International Name):
Sulfamethoxazole 80 mg/mL
Dosage:
480 mg/5mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Sulfamethoxazole 80 mg/mL   Trimethoprim 16 mg/mL Excipient: Propylene glycol Purified water
Units in package:
Ampoule, glass, Type I, clear, one point cut, 5 x 5ml, 25 mL
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Virchow Laboratories Limited
Product summary:
Package - Contents - Shelf Life: Ampoule, glass, Type I, clear, one point cut, 5 x 5ml - 25 mL - 36 months from date of manufacture stored at or below 30°C 24 hours opened stored at 2° to 8°C (Refrigerate, do not freeze)
Authorization number:
TT50-4193
Authorization date:
1987-06-18

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NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate Injection BP

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate Injection BP is an

antibacterial

combination

product,

containing

Trimethoprim

Sulfamethoxazole BP per mL in a 40 percent propylene glycol vehicle.

Excipient(s) with known effect

Sodium metabisulfite

Ethanol.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection

The solution is clear and has a pH of approximately 10.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Parenteral administration of sulfamethoxazole/trimethoprim is indicated where oral dosage is

not desirable or practical, eg pre- and post-operative infections associated with surgery, trauma

or gynaecology; septicaemia and other infections due to sensitive organisms such as typhoid

and paratyphoid.

4.2 Dose and method of administration

Dose

Dosage for Adults and Children over 12 years

Standard Dose: 10 mL diluted and infused twice daily.

For severe infections: 15 mL diluted and infused twice daily.

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Paediatric population

Dosage for Children to 12 years

The recommended dosage is approximately 6 mg trimethoprim and 30 mg sulfamethoxazole

per kg bodyweight per day, divided into two equal doses, morning and evening. As a guide,

the following doses of DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate

Injection BP may be used:

2 months to 5 months:

1.25 mL diluted and infused twice daily.

6 months to 5 years:

2.5 mL diluted and infused twice daily.

6 years to 12 years:

5 mL diluted and infused twice daily.

The recommended dosage for patients with documented

Pneumocystis jirovecii

pneumonia is

20 mg/kg trimethoprim and 100 mg/kg sulfamethoxazole per 24 hours given in equally divided

doses every 6 hours for 14 days.

Dose Adjustments

Renal Impairment

In patients with impaired renal function, the dosage and/or frequency of administration of

sulfamethoxazole/trimethoprim needs to be modified.

following

dosage

regimens

have

been

published

administration

sulfamethoxazole/trimethoprim tablets to patients with reduced kidney function. In view of

close

similarity

plasma

levels

trimethoprim

sulfamethoxazole

when

sulfamethoxazole/trimethoprim is given orally and intravenously, there is no reason to suppose

that these regimens cannot be followed with DBL Sulfamethoxazole 400 mg and Trimethoprim

80 mg Concentrate Injection BP.

Criteria of Kidney Function

(non-protein nitrogen is unsuitable)

Recommended Dosage Regimens

Creatinine

Clearance mL/min

Serum Creatinine

Micromol/L

(a)

One Standard Dose for Adults 160 mg TMP

+ 800 mg SMX

Above 25

Men < 260

Women < 170

Dosage as for patients with normal

kidney function, ie 1 standard dose

every 12 hours for up to 14 days;

thereafter half standard dose every

12 hours; no necessity of control

analyses of drugs in plasma.

25 - 15

Men 260 to 600

Women 170 to 400

One standard dose every 12 hours

for 3 days; thereafter one

standard dose every 24 hours for

as long as allowed by control

analyses

Below 15

Men > 600

Women > 400

Until further experience is gained,

the combination should be given

only if patients can undergo

haemodialysis when necessary

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(non-protein nitrogen is unsuitable)

Recommended Dosage Regimens

Creatinine

Clearance mL/min

Serum Creatinine

Micromol/L

(a)

One Standard Dose for Adults 160 mg TMP

+ 800 mg SMX

under this condition one standard

dose may be administered every

24 hours as long as allowed by

control analyses

Trimethoprim

Sulfamethoxazole

Serum creatinine levels can be used as the basis of dosing only in cases of stable chronic renal

impairment, but not acute or subacute kidney failure.

The concentration of total SMX should be measured in plasma samples obtained 12 hours after

every third day of treatment. Treatment must be interrupted if at any time the determined plasma

level of total SMX exceeds 150 micrograms/mL. As soon as the value of total SMX drops again

below 120 micrograms/mL (eg in patients undergoing haemodialysis), treatment can be continued

as recommended.

Both

trimethoprim

sulfamethoxazole

readily

dialysable,

leading

significantly

shortened half-life for each drug during dialysis. It is suggested that patients undergoing

haemodialysis receive a dose just before and at the end of the procedure.

Duration of treatment

DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate Injection BP should be

used ONLY during such periods as the patient is unable to accept oral therapy. In general,

administration is unlikely to be required for more than a few days, and it is recommended that

it be restricted to no more than three successive days.

Method of Administration

DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate Injection BP must be

diluted prior to administration. Sulfamethoxazole/trimethoprim

should be administered

intravenously only in the form of an infusion solution, and may not be injected undiluted either

intravenously or direct into the infusion tube.

DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate Injection BP may be

mixed only with the following infusion solutions:

5% Glucose Injection

4% Glucose/0.18% Sodium Chloride Injection

0.9% Sodium Chloride

10% Glucose Injection

2.5% Glucose/0.45% Sodium Chloride Injection

0.45% Sodium Chloride Injection

10% Dextran 40 in 5% Glucose

6% Dextran 70 in 0.9% Sodium Chloride Injection

Hartmann's Injection

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No other agent should be added to or mixed with the infusion.

It is important to adhere to the following minimum dilution scheme, which is based on a

proportion of 1 mL DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate

Injection BP to 25-30 mL infusion fluid. Add one ampoule (5 mL) to 125 mL infusion solution;

two ampoules (10 mL) to 250 mL infusion solution; or three ampoules (15 mL) to 500 mL

infusion solution or an equivalent dilution.

The prepared infusion should be shaken well to ensure thorough mixing. Should visible

turbidity or crystallisation appear in the solution during its preparation or infusion, it must be

discarded and replaced by a freshly prepared solution.

It is recommended that infusion of sulfamethoxazole/trimethoprim be commenced within half

an hour of preparation and the duration of infusion should not exceed 1.5 hours. However, this

should be balanced against the fluid requirements of the patient.

To reduce microbiological hazards the prepared diluted solution should in any case be used as

soon as practicable after preparation and within 24 hours. Do not refrigerate prepared solution.

4.3 Contraindications

Sulfamethoxazole/trimethoprim is contraindicated in patients with a history of drug-induced

immune thrombocytopenia with use of trimethoprim and/or sulphonamides and in patients

showing marked liver parenchymal damage, blood dyscrasias and severe renal insufficiency,

where repeated measurements of the plasma concentrations cannot be performed. It should not

be given to patients with known hypersensitivity to trimethoprim or sulfonamides or with

documented megaloblastic anaemia secondary to folate deficiency.

Premature babies and newborn babies during the first eight weeks of life should not be given

sulfamethoxazole/trimethoprim, as sulfamethoxazole may interfere with the serum albumin-

binding of bilirubin to produce kernicterus.

History of sulfonamide or trimethoprim sensitivity.

Treatment of streptococcal pharyngitis.

4.4 Special warnings and precautions for use

Hypersensitivity and allergic reactions

DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate Injection BP contains

sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis

and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The

overall prevalence of sulfite sensitivity in the general population is unknown and probably low;

such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Pulmonary infiltrates reported in the context of eosinophilic or allergic alveolitis may manifest

through symptoms such as cough or shortness of breath. Should such symptoms appear or

unexpectedly

worsen,

patient

should

re-evaluated

discontinuation

sulfamethoxazole/trimethoprim therapy considered.

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Serious adverse reactions

Fatalities, although rare, have occurred due to severe reactions including Stevens-

Johnson

syndrome,

toxic

epidermal

necrolysis,

fulminant

hepatic

necrosis,

agranulocytosis,

aplastic

anaemia

and

other

blood

dyscrasias.

Sulfamethoxazole/trimethoprim should be discontinued if a skin rash appears. Clinical

signs such as rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor,

purpura or jaundice may be early indications of serious reactions.

Sulfamethoxazole/trimethoprim-induced

thrombocytopenia

immune-mediated

disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported.

Thrombocytopenia

usually

resolves

within

week

upon

discontinuation

sulfamethoxazole/trimethoprim.

As with other sulfonamide preparations, critical appraisal of benefit versus risk should be made

in patients with liver damage, renal damage, urinary obstruction, blood dyscrasias, allergies or

bronchial asthma.

Use in treatment of Pneumocystis jirovecii pneumonia in Human Immunodeficiency Virus

(HIV) – positive patients

Because of their unique immune dysfunction, HIV-positive patients may not tolerate or respond

to sulfamethoxazole/trimethoprim in the same manner as non-

HIV-positive patients. The

incidence of side effects, particularly rash, fever, neutropenia, thrombocytopenia, raised liver

enzymes

leucopenia

necessitating

cessation

therapy,

with

sulfamethoxazole/trimethoprim therapy in HIV-positive patients who are being treated for

Pneumocystis jirovecii

pneumonia has been reported to be greatly increased compared with the

incidence normally associated with the use of sulfamethoxazole/trimethoprim in non-HIV-

positive patients. Such adverse effects have occurred in up to 80% of HIV-positive patients

receiving the drug, usually during the second week of therapy. The exact mechanism(s) of this

increased risk of sulfamethoxazole/trimethoprim toxicity has not been determined, but may be

immunologically based. These adverse effects usually recur following rechallenge with the

drug, although cautious desensitisation has been performed successfully in some patients in

whom continued sulfamethoxazole/trimethoprim therapy was considered necessary. Some

evidence indicates that sulfamethoxazole/trimethoprim may be better tolerated in HIV-infected

children than adults. Adverse effects are usually less severe in patients receiving the drug for

prophylaxis

Pneumocystis

jirovecii

pneumonia

compared

with

those

receiving

sulfamethoxazole/trimethoprim for treatment of the disease.

Use in glucose-6-phosphate dehydrogenase deficiency

In individuals with glucose-6-phosphate dehydrogenase deficiency, haemolysis may occur.

This may be dose related.

Pseudomembranous colitis

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics

including sulfamethoxazole and trimethoprim. A toxin produced with

Clostridium difficile,

appears to be the primary cause. The severity of the colitis may range from mild to life

threatening. It is important to consider this diagnosis in patients who develop diarrhoea or

colitis in association with antibiotic use (this may occur up to several weeks after cessation of

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antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in

moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective

against

Clostridium difficile

should be considered. Fluids, electrolytes and protein replacement

should

provided

when

indicated.

Drugs

which

delay

peristalsis

opiates

diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should

not be used.

Use in renal impairment

In renal impairment, a reduced or less frequent dosage is recommended in order to avoid

accumulation of trimethoprim in the blood. Non-ionic diffusion is the main factor in the renal

handling of trimethoprim, and as renal failure advances, trimethoprim excretion decreases. For

such patients, serum assays are necessary.

Patients with severe renal impairment who are receiving sulfamethoxazole/trimethoprim

should be closely monitored for symptoms and signs of toxicity such as nausea, vomiting and

hyperkalaemia. Sulfamethoxazole/trimethoprim should be given with caution to patients with

impaired renal function and to those with underlying disorders such as: possible folate

deficiency; hypoglycaemia; electrolyte abnormalities (hyperkalaemia).

Urinalysis with careful microscopic examination and renal function tests should be performed

frequently, particularly for those patients with impaired renal function. Adequate fluid intake

must be maintained in order to prevent crystalluria and stone formation. In patients with renal

impairment, a reduced or less frequent dosage is recommended to avoid accumulation of

trimethoprim in the blood.

Electrolyte abnormalities

Close monitoring of serum potassium and renal function is warranted in patients receiving

high-dose sulfamethoxazole/trimethoprim, as used in patients with

Pneumocystis jirovecii

pneumonia,

patients

receiving

standard-dose

sulfamethoxazole/trimethoprim

with

underlying disorders of potassium metabolism or renal insufficiency, or who are receiving

drugs which induce hyperkalaemia (see section 4.5). Severe and symptomatic hyponatremia

can occur in patients receiving sulfamethoxazole/trimethoprim, particularly for the treatment

P. jirovecii

pneumonia. Evaluation for hyponatremia and appropriate correction is necessary

in symptomatic patients to prevent life-threatening complications.

Folate deficiency

Because of the possible interference with folate metabolism, regular blood counts are advisable

in patients on long-term therapy, in those who are pre-disposed to folate deficiency (i.e. the

elderly, chronic alcoholics and those with rheumatoid arthritis), in malabsorption syndromes,

malnutrition states or during the treatment of epilepsy with anticonvulsant drugs such as

phenytoin,

primidone

barbiturates.

Folic

acid

administered

during

sulfamethoxazole/trimethoprim therapy and will not interfere with the drugs antibacterial

effect. Megaloblastic anaemia and occasionally neutropenia and thrombocytopenia may be

reversed by administration of calcium leucovorin (folinic acid). If signs of bone marrow

suppression occur in patients receiving sulfamethoxazole/trimethoprim, leucovorin may be

administered.

The possibility of superinfection with a non-sensitive organism should be borne in mind.

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Use in the elderly

The use of sulfamethoxazole/trimethoprim in elderly patients carries an increased risk of severe

adverse reactions. In rare instances fatalities have occurred. The risk of severe adverse

reactions is particularly greater when complicating conditions exist, eg impaired kidney and/or

liver function, or concomitant use of other drugs. Severe skin reactions, or generalised bone

marrow suppression (see section 4.8) or a specific decrease in platelets (with or without

purpura) are the most frequently reported severe adverse reactions in elderly patients. In those

concurrently

receiving

certain

diuretics,

primarily

thiazides,

increased

incidence

thrombocytopenia with purpura has been reported. Appropriate dosage adjustments should be

made for patients with impaired kidney function (see section 4.2).

In view of the increased risk of severe adverse reactions in the elderly, consideration should be

given to whether sulfamethoxazole/trimethoprim is the antibacterial of choice in this age group.

Effects on laboratory tests

Two laboratory procedures, namely the

Lactobacillus casei

serum folate assay and the

L.

leishmanii

serum vitamin B

assay are affected by sulfamethoxazole/trimethoprim.

Sulfamethoxazole/trimethoprim, specifically the trimethoprim component, can interfere with a

serum methotrexate assay as determined by the competitive binding protein technique when a

bacterial dihydrofolate reductase is used as the binding protein. No interference occurs,

however, if methotrexate is measured by a radioimmunoassay.

The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaffe alkaline

picrate reaction assay for creatinine, resulting in overestimations of about 10% of the range of

normal values.

Paediatric population

See sections 4.2 and 4.3.

4.5 Interaction with other medicines and other forms of interaction

Methotrexate: Sulfonamides such as sulfamethoxazole may displace methotrexate from

protein binding sites, thereby increasing free methotrexate levels. Cases of pancytopenia have

been reported in patients taking the combination of sulfamethoxazole/trimethoprim and

methotrexate.

Para-aminobenzoic acid (

PABA) or its derivatives: may antagonise the antibacterial effects

of sulfamethoxazole.

Urinary acidifiers: Increased sulfamethoxazole blood levels may occur in patients who are also

receiving

urinary

acidifiers,

oral

anticoagulants,

phenylbutazone,

oxyphenbutazone

indomethacin.

Warfarin:

Anticoagulant

activity

increased

concurrent

treatment

with

sulfamethoxazole/trimethoprim.

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Phenytoin: Increased effects and side effects of phenytoin (folate deficiencies) could occur

when sulfamethoxazole/trimethoprim is given concurrently.

Cross sensitisation may exist between sulfamethoxazole/trimethoprim and some antithyroid

agents, diuretics (acetazolamide and the thiazides) and oral hypoglycaemic drugs.

Sulphonylureas: Concomitant use may result in potentiation of hypoglycaemia in occasional

patients.

Diuretics: An increased incidence of thrombocytopenia is reported when this combination is

used in the elderly.

Cyclosporin: Deterioration in renal function in patients with renal transplants.

Pyrimethamine: Occasional reports suggest that patients receiving pyrimethamine as malarial

prophylaxis at doses in excess of 25 mg weekly may develop megaloblastic anaemia should

sulfamethoxazole/trimethoprim be prescribed concurrently.

Digoxin: Concomitant use of trimethoprim with digoxin has been shown to increase plasma

digoxin levels in a proportion of elderly patients.

Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, potassium sparing

diurietcs,

prednisolone:

potassium

sparing

effects

sulfamethoxazole/trimethoprim, caution should be used when other agents that increase serum

potassium, such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers,

potassium sparing diuretics and prednisolone, are co-administered (see section 4.4).

Others: When trimethoprim is administered simultaneously with drugs that form cations at

physiological pH, and are also partly excreted by active renal secretion (eg procainamide,

amantadine), there is the possibility of competitive inhibition of this process which may lead

to an increase in plasma concentration of one or both of the drugs.

4.6 Fertility, pregnancy and lactation

Fertility

No data available.

Pregnancy - Category C

Category C = Drugs which, owing to their pharmacological effects, have caused or may be

suspected of causing, harmful effects on the human

fetus or neonate

without causing

malformations. These effects may be reversible.

Sulfonamides may cause kernicterus in babies during the first month of life by displacing

bilirubin from plasma albumin. Sulfonamides should therefore be avoided as far as possible

during the last month of pregnancy. Trimethoprim may interfere with folic acid metabolism

and animal experiments have shown that administration of very high doses of trimethoprim

during organ development may give rise to birth defects typical of folic acid antagonism. If a

trimethoprim-sulfonamide combination is given during pregnancy, folic acid supplementation

may be required.

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Lactation

Both trimethoprim and sulfamethoxazole are

excreted in breast

milk at concentrations

comparable

somewhat

lower

than

those

blood.

Although

quantity

sulfamethoxazole/trimethoprim ingested by a breast-fed infant is small, it is recommended that

the age of the infant be considered and the possible risks be balanced against the expected

therapeutic effect.

4.7 Effects on ability to drive and use machinery

The effects of this medicine on a person’s ability to drive and use machines were not assessed

as part of its registration.

4.8 Undesirable effects

Fatalities, although rare, have occurred due to severe reactions including Stevens-Johnson

syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocystosis, aplastic

anaemia and other blood dyscrasias. Sulfamethoxazole/trimethoprim should be discontinued

if a skin rash appears. Clinical signs such as rash, sore throat, fever, arthralgia, cough, shortness

of breath, pallor, purpura or jaundice may be early indications of serious reactions.

Adverse reactions have been reported in approximately 5-7% of patients treated in the

published literature. In general, the adverse reactions correspond to those of a sulfonamide of

moderately low toxicity.

Gastrointestinal: Nausea and vomiting are the most frequent gastrointestinal reactions to

sulfamethoxazole/trimethoprim,

glossitis,

stomatitis,

abdominal

pain,

pancreatitis,

pseudomembranous colitis and diarrhoea have also been reported.

Haematological: Haematological changes have been observed in some patients, particularly the

elderly. The great majority of these changes were mild, asymptomatic and proved reversible

on withdrawal of the drug. The reported changes consist primarily of neutropenia and

thrombocytopenia. Leucopenia, eosinophilia, megaloblastic anaemia, methaemoglobinaemia,

hypothrombinaemia, aplastic and haemolytic anaemia, purpura, agranulocytosis and bone

marrow depression have been observed less frequently. Haematological toxicity may occur

with

increased

frequency

folate-depleted

patients

including

geriatric,

malnourished,

alcoholic, pregnant or debilitated patients; in patients receiving anti-folates (eg phenytoin or

methotrexate) or diuretics; in patients with haemolysis or impaired renal function; and in

patients receiving sulfamethoxazole/trimethoprim in high dosages and/or for prolonged periods

(eg longer than 6 months). In geriatric patients receiving some diuretics (principally thiazides)

sulfamethoxazole/trimethoprim

concomitantly,

increased

incidence

thrombocytopenia with purpura has been reported. The risk of leucopenia, neutropenia and

thrombocytopenia also appear to be increased in HIV-positive patients.

High doses of trimethoprim as used in patients with

Pneumocystis jirovecii

pneumonia induces

progressive but reversible increase of serum potassium concentration in a substantial number

patients.

Even

treatment

with

recommended

doses

cause

hyperkalaemia

when

trimethoprim is administered to patients with underlying disorders of potassium metabolism,

with renal insufficiency, or if drugs known to induce hyperkalaemia are given concomitantly.

Cases of hyponatraemia have also been reported (see section 4.4).

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Sensitivity reactions: Several cases of Stevens-Johnson syndrome (erythema multiforme

bullosa) and Lyell's syndrome (toxic epidermal necrolysis) have been reported. Together with

exfoliative dermatitis, serum sickness and allergic myocarditis, these are the most severe

allergic reactions reported with sulfonamides alone, or in combination with trimethoprim.

Other reported allergic and anaphylactoid reactions include anaphylaxis, arthralgia, erythema

multiforme, Schönlein-Henoch purpura, pruritis, urticaria, periorbital oedema, corneal ring

infiltrates, conjunctival and scleral redness and oedema, and photosensitivity. Mild to

moderate rashes, when they occur, usually appear within 7-14 days after initiation of

sulfamethoxazole/trimethoprim.

Rashes

generally

erythematous,

maculopapular,

morbilliform, and/or pruritic. Generalised pustular dermatosis and fixed drug eruption have

also been reported. HIV-positive patients appear to be at particular risk of developing rash

(usually diffuse, erythematous and maculopapular) during sulfamethoxazole/trimethoprim

therapy.

Hepatic: Hepatic changes (as indicated by abnormal elevations in alkaline phosphatase and

serum transaminase levels) including hepatic necrosis have been reported rarely and may be

fatal. Jaundice rarely occurs and has usually been mild and transient, frequently occurring in

patients with a past history of infectious hepatitis. Elevation of bilirubin levels has also been

reported.

Genitourinary: Dysuria, oliguria, anuria, haematuria, urgency and functional kidney changes

(as indicated by abnormal elevations in serum urea, serum creatinine and urine protein

concentrations) have been reported occasionally. Renal failure, interstitial nephritis and toxic

nephrosis have been reported. Crystalluria and stone formation have occurred in patients

receiving sulfamethoxazole/trimethoprim. Diuresis has occurred rarely in patients receiving

sulfonamides.

Central nervous system: Adverse nervous system effects of sulfamethoxazole/trimethoprim

include headache, insomnia, fatigue, apathy, nervousness, muscle weakness, ataxia, vertigo,

tinnitus, peripheral neuritis, mental depression, aseptic meningitis, seizures and hallucinations.

Tremor and other neurologic manifestations (eg ataxia, ankle clonus, apathy) developed during

sulfamethoxazole/trimethoprim

therapy

several

HIV-positive

patients;

although

such

manifestations have also been associated with the underlying disease process, they resolved in

these patients within 2-3 days after discontinuing the drug.

Local effects: Pain, local irritation, inflammation, and thrombophlebitis may occasionally

occur with intravenous sulfamethoxazole/trimethoprim, especially if extravasation of the drug

occurs.

Skin

subcutaneous

tissue

disorders:

Drug

reaction

with

eosinophilia

systemic

symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP).

Miscellaneous: Other adverse effects reported with sulfamethoxazole/trimethoprim include

drug fever, chills, myalgia, pulmonary infiltrates, cough, shortness of breath, hypotension,

periarteritis nodosa and a positive lupus erythematous phenomenon. Vision problems, alopecia

and epistaxis have been reported rarely.

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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 are

asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

Symptoms

Overdosage with sulfamethoxazole/trimethoprim may produce symptoms of nausea, vomiting,

mental and visual disturbances, petechiae, purpura, pyrexia, haematuria and crystalluria. Blood

dyscrasias and jaundice are late complications.

Treatment

Stop therapy. Force fluids orally or parenterally if renal function is normal. In extreme

overdosage

patients

with

impaired

renal

function,

consider

haemodialysis

which

moderately effective in removing sulfamethoxazole and trimethoprim. Peritoneal dialysis is

ineffective.

No known antidote for sulfonamide poisoning exists, however, calcium folinate (the equivalent

of 3 mg to 6 mg folinic acid intramuscularly for 5 to 7 days) is an effective antidote for adverse

effects in the haemopoietic system caused by trimethoprim.

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

Mechanism of action

Sulfamethoxazole/trimethoprim interferes with the bacterial synthesis of tetrahydrofolic acid,

an essential stage in the production of thymidine, purines and subsequently nucleic acids.

Sulfamethoxazole inhibits the formation of dihydrofolic acid from p-aminobenzoic acid;

trimethoprim inhibits the action of the enzyme dihydrofolate reductase, thus preventing the

synthesis of tetrahydrofolic acid from dihydrofolic acid. Thus the combination of trimethoprim

and sulfamethoxazole blocks two consecutive steps within the bacterial metabolic pathway of

the biosynthesis of nucleic acids and proteins.

Sulfamethoxazole/trimethoprim usually shows in vitro activity against the following gram-

negative

gram-positive

organisms,

E.

coli,

Neisseria,

Salmonella,

Klebsiella-

Enterobacter, Shigella, Vibrio cholerae, Bordetella pertussis, Streptococcus, Staphylococcus,

Pneumococcus, Haemophilus influenzae

Proteus.

Sulfamethoxazole/trimethoprim is also active against the protozoan

Pneumocystis jirovecii.

However,

Mycobacterium tuberculosis, Treponema pallidum, Mycoplasma

Pseudomonas

aeruginosa

are frequently resistant to sulfamethoxazole/trimethoprim.

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5.2 Pharmacokinetic properties

Distribution

Concentrations

least

microgram/mL

trimethoprim

microgram/mL

sulfamethoxazole are reached within 30 minutes after the start of an infusion and are

maintained

least

hours.

Mean

peak

steady-state

serum

concentrations

approximately 9 and 105 micrograms/mL of trimethoprim and sulfamethoxazole, respectively,

reached

after

intravenous

(IV)

infusion

trimethoprim

sulfamethoxazole every 8 hours in adults with normal renal function. Steady-state trough

concentrations reached with this intravenous (IV) dose are approximately 6 microgram/mL of

trimethoprim

microgram/mL

sulfamethoxazole.

administration

trimethoprim/sulfamethoxazole

ratio

achieves

trimethoprim/sulfamethoxazole

concentrations in the blood of about 1:20.

Sulfamethoxazole/trimethoprim is widely distributed into body tissues. Sulfamethoxazole is

distributed mainly in the extracellular body fluids while trimethoprim, which has lipophilic

properties, concentrates in the tissues. Approximately 44% of trimethoprim and 70% of

sulfamethoxazole are protein bound in the blood.

Biotransformation

Sulfamethoxazole/trimethoprim is metabolised in the liver. Trimethoprim is metabolised to

oxide and hydroxylated metabolites, while sulfamethoxazole is acetylated and conjugated with

glucuronic acid.

Elimination

Sulfamethoxazole/trimethoprim is rapidly excreted in the urine.

5.3 Preclinical safety data

Genotoxicity

No data available.

Carcinogenicity

No data available.

Reproductive and developmental toxicity

No data available.

6.

PHARMACEUTICAL PARTICUALRS

6.1 List of excipients

Diethanolamine

Propylene glycol

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Ethanol

Sodium metabisulfite

Sodium hydroxide (for pH-adjustment)

Hydrochloric acid (for pH-adjustment)

Water for injections

6.2 Incompatibilities

This medicine must not be mixed with other medicines except those mentioned in section 6.6.

6.3 Shelf life

36 months

24 hours opened stored at 2° to 8°C (Refrigerate, do not freeze)

6.4 Special precautions for storage

Store below 30°C. Do not refrigerate. Protect from light.

If stored at low temperatures precipitation may occur, and solutions in which precipitation has

occurred should be discarded.

6.5 Nature and contents of container

Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate Injection BP is

supplied as a 5 mL ampoule containing 400 mg sulfamethoxazole and 80 mg trimethoprim in

packs of 5 ampoules.

6.6 Special precautions for disposal and other handling

Compatibilities

DBL Sulfamethoxazole 400 mg and Trimethoprim 80 mg Concentrate Injection BP has been

found to be stable for 24 hours at room temperature under fluorescent light when admixed with

the following solutions at a dilution of 1 in 25 and 1 in 35.

5% Glucose Injection

4% Glucose/0.18% Sodium Chloride Injection

0.9% Sodium Chloride Injection

10% Glucose Injection

2.5% Glucose/0.45% Sodium Chloride Injection

0.45% Sodium Chloride Injection

Dextran 70 6% in 0.9% Sodium Chloride Injection

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Dextran 40 10% in 5% Glucose

No other agent should be added to or mixed with the infusion.

When admixed with Hartmann's Injection, DBL Sulfamethoxazole 400 mg and Trimethoprim

80 mg Concentrate Injection BP has been found to be stable for 8 hours at a 1 in 25 dilution

and for 24 hours at a 1 in 35 dilution.

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

7.

MEDICINE SCHEDULE

Prescription Medicine

8.

SPONSOR

Pfizer New Zealand Limited

PO Box 3998

Auckland, New Zealand, 1140

Toll Free Number: 0800 736 363

9.

DATE OF FIRST APPROVAL

18 June 1987

10. DATE OF REVISION OF THE TEXT

9 January 2020

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Minor editorial changes

Addition of adverse effects DRESS and AGEP.

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