SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Septrin 16 mg/80 mg per ml for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml of Septrin 16 mg/80 mg per ml for Infusion contains 80 mg Trimethoprim and 400 mg Sulfamethoxazole.

Excipients:

This product contains 1.7mmoles of sodium and 13.2 vol % ethanol (alcohol) per 5 ml.

For a full list of excipients, see Section 6.1

3 PHARMACEUTICAL FORM

Solution for Infusion A clear liquid.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Septrin for Infusion is indicated for the treatment of the following infections when owing to sensitive organisms (see section 5.1):

Acute uncomplicated urinary tract infection.

It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than a combination such as Septrin for Infusion.

Treatment and prevention of Pneumocystis jiroveci pneumonitis (previously known as Pneumocystis carinii pneumonia or “PCP”)

Treatment and prophylaxis of toxoplasmosis.

Treatment of nocardiosis.

In general, the indications for the use of Septrin for Infusion are the same as those for oral presentations.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Method of Administration: Septrin for Infusion is for administration only by the intravenous route and must be diluted before administration.

It is intended that Septrin for Infusion should be used only during such a period as the patient is unable to accept oral therapy, where initiation of treatment is particularly urgent or for convenience if the patient is already receiving intravenous fluids. Although Septrin for Infusion is useful in critically ill patients, there may be no therapeutic advantage over the oral preparation.

For instructions on dilution of the product before administration, see section 6.6. Standard dosage recommendations for acute infections

Adults and children over 12 years:

2 ampoules (10 ml) every 12 hours.

Children aged 12 years and under:

The recommended dosage is approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kg bodyweight per 24 hours, given in two equally divided doses. As a guide the following schedules may be used diluted as described above.

For severe infections in all age groups, dosage may be increased by 50%.

Treatment should be continued until the patient has been symptom free for two days; the majority will require treatment for at least 5 days.

The elderly:

See Special Warnings and Precautions for Use.

Impaired hepatic function:

No data are available relating to dosage in patients with impaired hepatic function.

Special Dosage Recommendations

(Standard dosage applies unless otherwise specified)

Impaired renal function:

Adults and children over 12 years (no information is available for children under 12 years of age):

Creatinine Clearance (ml/min)	Recommended Dosage
More than 30	STANDARD DOSAGE
15-30	Half the STANDARD DOSAGE
Less than 15	Not recommended

Measurements of plasma concentrations of sulfamethoxazole at intervals of 2 to 3 days are recommended in samples obtained 12 hours after administration of Septrin 16 mg/80 mg per ml for Infusion. If the concentration of total sulfamethoxazole exceeds 150 micrograms/ml then treatment should be interrupted until the value falls below 120 micrograms/ml.

Pneumocystis jiroveci (P. carinii) pneumonitis:

Treatment

20 mg trimethoprim and 100 mg sulfamethoxazole per kg of bodyweight per day in two or more divided doses. Therapy should be changed to the oral route as soon as possible and continued for a total treatment period of two weeks. The aim is to obtain peak plasma or serum levels of trimethoprim of greater than or equal to 5 microgram/ml (verified in patients receiving 1-hour infusions of intravenous Septrin). (See 4.8 Undesirable Effects)

Prevention

Standard dosage for the duration of the period at risk.

Nocardiosis: There is no consensus on the most appropriate dosage. Adult doses of 6 to 8 tablets daily for up to 3 months have been used (one tablet contains 400 mg sulfamethoxazole and 80 mg trimethoprim).

Toxoplasmosis: There is no consensus on the most appropriate dosage for the treatment or prophylaxis of this condition. The decision should be based on clinical experience. For prophylaxis, however, the dosages suggested for prevention of Pneumocystis jiroveci pneumonitis may be appropriate.

4.3 Contraindications

Septrin for Infusion should not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim, co-trimoxazole or any excipients of Septrin.

Septrin for Infusion is contra-indicated in patients showing marked liver parenchymal damage.

Septrin for Infusion is contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

Septrin for Infusion should not be given to premature babies nor to full-term infants during the first six weeks of life except for the treatment/prophylaxis of PCP in infants 4 weeks of age or greater.

4.4 Special Warnings and Precautions for Use

Fatalities, although very rare, have occurred due to severe reactions including fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.

•    Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Septrin.

•    Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

•    If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Septrin treatment should be discontinued (see 4.8 Undesirable Effects).

•    The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

•    If the patient has developed SJS or TEN with the use of Septrin, Septrin must not be re-started in this patient at any time.

Fluid overload is possible, especially when very high doses are being administered to patients with underlying cardiopulmonary disease.

An adequate urinary output should be maintained at all times. Evidence of crystalluria in vivo is rare, although sulphonamide crystals have been noted in cooled urine from treated patients. In patients suffering from malnutrition the risk may be increased.

For patients with known renal impairment special measures should be adopted (See 4.2 Posology and Method of Administration).

Regular monthly blood counts are advisable when Septrin is given for long periods, or to folate deficient patients or to the elderly since there exists a possibility of asymptomatic changes in haematological laboratory indices due to lack of available folate. These changes may be reversed by administration of folinic acid (5 to 10 mg/day) without interfering with the antibacterial activity.

Particular care is always advisable when treating elderly patients because, as a group, they are more susceptible to adverse reactions and more likely to suffer serious side effects as a result, particularly when complicating conditions exist, e.g. impaired kidney and/or liver function and/or concomitant drugs.

In glucose-6-phosphate dehydrogenase-deficient (G-6-PD) patients, haemolysis may occur.

Septrin should be given with caution to patients with severe allergy or bronchial asthma.

Septrin should not be used in the treatment of streptococcal pharyngitis due to Group A beta-haemolytic streptococci. Eradication of these organisms from the oropharynx is less effective than with penicillin.

Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

The administration of Septrin to patients known or suspected to be at risk of acute porphyria should be avoided. Both trimethoprim and sulphonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria.

Close monitoring of serum potassium and sodium is warranted in patients at risk of hyperkalaemia and hyponatraemia.

This medicinal product contains 13.2 vol% ethanol (alcohol), i.e. up to 521 mg per dose. This is equivalent to 2.64 ml of beer, or 1.1 ml of wine. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

This medicinal product contains sodium metabisulphite, which may rarely cause severe hypersensitivity reaction and bronchospasm.

This medicinal product contains 1.7 mmoles (or 38.87 mg) of sodium. To be taken into consideration by patients on a sodium controlled diet.

Except under careful supervision Septrin for Infusion should not be given to patients with serious haematological disorders (see 4.8 Undesirable Effects). Septrin has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.

The combination of the antibiotics in Septrin for Infusion should only be used where, in the judgement of the physician, the benefits of treatment outweigh any possible risks; consideration should be given to the use of a single effective antibacterial agent.

4.5 Interaction with other medicinal products and other forms of interaction

Trimethoprim may interfere with the estimation of serum/plasma creatinine when the alkaline picrate reaction is used. This may result in overestimation of serum/plasma creatinine of the order of 10%. The creatinine clearance is reduced: the renal tubular secretion of creatinine is decreased from 23% to 9% whilst the glomerular filtration remains unchanged.

In some situations, concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to co-trimoxazole. If concomitant treatment is necessary, consideration should be given to monitoring of haematological parameters.

Reversible deterioration in renal function has been observed in patients treated with co-trimoxazole and ciclosporin following renal transplantation.

Concurrent use of rifampicin and Septrin results in a shortening of the plasma halflife of trimethoprim after a period of about one week. This is not thought to be of clinical significance.

When trimethoprim is administered simultaneously with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. 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.

In elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.

Occasional reports suggest that patients receiving pyrimethamine as malarial prophylaxis at doses in excess of 25 mg weekly may develop megaloblastic anaemia should co-trimoxazole be prescribed concurrently.

Co-trimoxazole has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulfamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro. Careful control of the anticoagulant therapy during treatment with Septrin is advisable.

Co-trimoxazole prolongs the half-life of phenytoin and if co-administered the prescriber should be alert for excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels is advisable.

Concomitant use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in a proportion of elderly patients.

Co-trimoxazole may increase the free plasma levels of methotrexate.

Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacillus casei is used in the assay. No interference occurs if methotrexate is measured by radioimmuno assay.

Administration of trimethoprim/sulfamethoxazole 160mg/800mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.

Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reported.

Caution should be exercised in patients taking any other drugs that can cause hyperkalaemia.

If Septrin is considered appropriate therapy in patients receiving other anti-folate drugs such as methotrexate, a folate supplement should be considered.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are not any adequate data from the use of Septrin for Infusion in pregnant women. Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans.

Trimethoprim is a folate antagonist and, in animal studies, both agents have been shown to cause foetal abnormalities (see 5.3 Preclinical Safety Data).

Septrin for Infusion should not be used in pregnancy, particularly in the first trimester, unless clearly necessary. Folate supplementation should be considered if Septrin for Infusion is used in pregnancy.

Sulfamethoxazole competes with bilirubin for binding to plasma albumin. As significantly maternally derived drug levels persist for several days in the newborn, there may be a risk of precipitating or exacerbating neonatal hyperbilirubinaemia, with an associated theoretical risk of kernicterus, when Septrin for Infusion is administered to the mother near the time of delivery. This theoretical risk is particularly relevant in infants at increased risk of hyperbilirubinaemia, such as those who are preterm and those with glucose-6-phosphate dehydrogenase deficiency.

Lactation

The components of Septrin for Infusion (trimethoprim and sulfamethoxazole) are excreted in breast milk. Administration of Septrin for Infusion should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilirubinaemia. Additionally, administration of Septrin for Infusion should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable Effects

As co-trimoxazole contains trimethoprim and a sulphonamide the type and frequency of adverse reactions associated with such compounds are expected to be consistent with extensive historical experience.

Data from large published clinical trials were used to determine the frequency of very common to rare adverse events. Very rare adverse events were primarily determined from post-marketing experience data and therefore refer to reporting rate rather than a "true" frequency. In addition, adverse events may vary in their incidence depending on the indication.

The following convention has been used for the classification of adverse events in terms of frequency:- Very common >1/10, common >1/100 and <1/10, uncommon >1/1000 and <1/100, rare >1/10,000 and <1/1000, very rare <1/10,000.

Infections and Infestations

Common:    Monilial overgrowth

Blood and lymphatic system disorders

Very rare:    Leucopenia, neutropenia, thrombocytopenia, agranulocytosis,

megaloblastic anaemia, aplastic anaemia, haemolytic anaemia, methaemoglobinaemia, eosinophilia, purpura, haemolysis in certain susceptible G-6-PD deficient patients

Immune system disorders

Very rare:    Serum sickness, anaphylaxis, allergic myocarditis, angioedema,

drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus

Metabolism and nutrition disorders

Very common: Hyperkalaemia

Very rare:    Hypoglycaemia, hyponatraemia, anorexia

Psychiatric disorders

Very rare:    Depression, hallucinations

Nervous system disorders

Common:    Headache

Very rare:    Aseptic meningitis, convulsions, peripheral neuritis, ataxia,

vertigo, tinnitus, dizziness

Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred in a number of cases on re-exposure to either co-trimoxazole or to trimethoprim alone.

Respiratory, thoracic and mediastinal disorders

Cough, shortness of breath, pulmonary infiltrates

Cough, shortness of breath and pulmonary infiltrates may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal.

Gastrointestinal disorders

Common:    Nausea, diarrhoea

Uncommon:    Vomiting

Very rare:    Glossitis, stomatitis, pseudomembranous colitis, pancreatitis

Eye Disorders

Very rare:    Uveitis

Hepatobiliary disorders

Very rare:    Elevation of serum transaminases, elevation of bilirubin levels,

cholestatic jaundice, hepatic necrosis

Cholestatic jaundice and hepatic necrosis may be fatal.

Skin and subcutaneous tissue disorders

Common:    Skin rashes

Very rare: Photosensitivity, exfoliative dermatitis, fixed drug eruption, erythema multiforme, severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4)

Musculoskeletal and connective tissue disorders Very rare:    Arthralgia, myalgia

Renal and urinary disorders

Very rare:    Impaired renal function (sometimes reported as renal failure),

interstitial nephritis

Effects associated with Pneumocystis jiroveci (P.carinii) Pneumonitis (PCP) management

Very rare:    Severe hypersensitivity reactions, rash, fever, neutropenia,

thrombocytopenia, raised liver enzymes, hyperkalaemia, hyponatraemia, rhabdomyolysis.

At the high dosages used for PCP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. If signs of bone marrow depression occur, the patient should be given calcium folinate supplementation (5-10 mg/day). Severe hypersensitivity reactions have been reported in PCP patients on re-exposure to co-trimoxazole, sometimes after a dosage interval of a few days. Rhabdomyolysis has been reported in HIV positive patients receiving co-trimoxazole for prophylaxis or treatment of PCP.

4.9 Overdose

The maximum tolerated dose in humans is unknown.

Nausea, vomiting, dizziness and confusion are likely symptoms of overdosage. Bone marrow depression has been reported in acute trimethoprim overdosage.

In cases of known, suspected or accidental overdosage, stop therapy.

Dependent on the status of renal function, administration of fluids is recommended if urine output is low.

Both trimethoprim and active sulfamethoxazole are dialysable by renal dialysis. Peritoneal dialysis is not effective.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Combinations of sulfonamides and trimethoprim, incl. derivatives; ATC code: J01EE01

Mode of Action

Septrin is an antibacterial drug composed of two active principles, sulfamethoxazole and trimethoprim. Sulfamethoxazole is a competitive inhibitor of dihydropteroate synthetase enzyme. Sulfamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid (PABA) in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim binds to and reversibly inhibits bacterial dihydrofolate reductase (DHFR) and blocks the production of tetrahydrofolate. Depending on the conditions the effect may be bactericidal. Thus trimethoprim and sulfamethoxazole block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents.

Mechanism of resistance

In vitro studies have shown that bacterial resistance can develop more slowly with both sulfamethoxazole and trimethoprim in combination that with either sulfamethoxazole or trimethoprim alone.

Resistance to sulfamethoxazole may occur by different mechanisms. Bacterial mutations cause an increase the concentration of PABA and thereby out-compete with sulfamethoxazole resulting in a reduction of the inhibitory effect on dihydropteroate synthetase enzyme. Another resistance mechanism is plasmid-mediated and results from production of an altered dihydropteroate synthetase enzyme, with reduced affinity for sulfamethoxazole compared to the wild-type enzyme.

Resistance to trimethoprim occurs through a plasmid-mediated mutation which results in production of an altered dihydrofolate reductase enzyme having a reduced affinity for trimethoprim compared to the wild-type enzyme.

Trimethoprim binds to plasmodial DHFR but less tightly than to bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.

Many common pathogenic bacteria are susceptible in vitro to trimethoprim and sulfamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antibiotics, however, in vitro activity does not necessarily imply that clinical efficacy has been demonstrated and it must be noted that satisfactory susceptibility testing is achieved only with recommended media free from inhibitory substances, especially thymidine and thymine.

Breakpoints

EUCAST

Enterobacteriaceae: S< 2 R> 4 S. maltophilia: S< 4 R> 4 Acinetobacter: S< 2 R> 4 Staphylococcus: S< 2 R> 4 Enterococcus: S< 0.032 R> 1 Streptococcus ABCG: S< 1 R> 2 Streptococcus pneumoniae: S< 1 R> 2 Hemophilus influenza: S< 0.5 R> 1 Moraxella catarrhalis: S<0.5 R >1

Psuedomonas aeruginosa and other non-enterobacteriaceae: S< 2* R> 4*

S = susceptible, R = resistant. *These are CLSI breakpoints since no EUCAST breakpoints are currently available for these organisms.

Trimethoprim: sulfamethoxazole in the ratio 1:19. Breakpoints are expressed as trimethoprim concentration.

Antibacterial Spectrum

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. This information gives only an approximate guidance on probabilities whether microorganisms will be susceptible to trimethoprim/sulfamethoxazole or not.

Trimethoprim/sulfamethoxazole susceptibility against a number of bacteria are shown in the table below:

Commonly susceptible species:

Gram-positive aerobes:

Staphylococcus aureus Staphylococcus saprophyticus Streptococcus pyogenes Gram-negative aerobes:

Enterobacter cloacae Haemophilus influenzae Klebsiella oxytoca Moraxella catarrhalis Salmonella spp.

Stenotrophomonas maltophilia Yersinia spp.

Species for which acquired resistance may be a problem:

Gram-positive aerobes:

Enterococcus faecalis Enterococcus faecium Nocardia spp.

Staphylococcus epidermidis Streptococcus pneumoniae

Gram-negative aerobes:

Citrobacter spp.

Enterobacter aerogenes Escherichia coli Klebsiella pneumoniae Klebsiella pneumonia Proteus mirabilis Proteus vulgaris Providencia spp.

Serratia marcesans Inherently resistant organisms:

Gram-negative aerobes:

Pseudomonas aeruginosa

5.2 Pharmacokinetic properties

Peak plasma levels of trimethoprim and sulfamethoxazole are higher and achieved more rapidly after one hour of intravenous infusion of Septrin 16 mg/80 mg per ml for Infusion than after oral administration of an equivalent dose of a Septrin oral presentation. Plasma concentrations, elimination halflife and urinary excretion rates show no significant differences following either the oral or intravenous route of administration.

Trimethoprim is a weak base with a pKa of 7.3. It is lipophilic. Tissue levels of trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations. Trimethoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, sputum, and vaginal secretions. Levels in the aqueous humor, breast milk, cerebrospinal fluid, middle ear fluid, synovial fluid and tissue (interstitial) fluid are adequate for antibacterial activity. Trimethoprim passes into amniotic fluid and fetal tissues reaching concentrations approximating those of maternal serum.

Approximately 50% of trimethoprim in the plasma is protein bound. The halflife in man is in the range 8.6 to 17 hours in the presence of normal renal function. It is increased by a factor of 1.5 to 3.0 when the creatinine clearance is less than 10 ml/minute. There appears to be no significant difference in the elderly compared with young patients.

The principal route of excretion of trimethoprim is renal and approximately 50% of the dose is excreted in the urine within 24 hours as unchanged drug. Several metabolites have been identified in the urine. Urinary concentrations of trimethoprim vary widely.

Sulfamethoxazole is a weak acid with a pKa of 6.0. The concentration of active sulfamethoxazole in amniotic fluid, aqueous humor, bile, cerebrospinal fluid, middle ear fluid, sputum, synovial fluid and tissue (interstitial) fluid is of the order of 20 to 50% of the plasma concentration. Approximately 66% of sulfamethoxazole in the plasma is protein bound. The half-life in man is approximately 9 to 11 hours in the presence of normal renal function. There is no change in the half-life of active sulfamethoxazole with a reduction in renal function but there is prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25 ml/minute.

The principal route of excretion of sulfamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form. In elderly patients there is a reduced renal clearance of sulfamethoxazole.

5.3 Preclinical safety data

Reproductive toxicology: At doses in excess of recommended human therapeutic dose, trimethoprim and sulfamethoxazole have been reported to cause cleft palate and other foetal abnormalities in rats, findings typical of a folate antagonist. Effects with trimethoprim were preventable by administration of dietary folate. In rabbits, foetal loss was seen at doses of trimethoprim in excess of human therapeutic doses.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Propylene Glycol (E1520)

Tromethamine Sodium Hydroxide (E524)

Sodium Metabisulphite (E223)

Ethanol

Water for Injections

6.2 Incompatibilities

None known.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store below 30°C. Protect from light.

6.5 Nature and contents of container

Neutral glass ampoules (5ml nominal fill volume) Pack size: 10 x 5ml ampoules

6.6 Special precautions for disposal

Septrin for Infusion must be diluted before administration.

Dilution should be carried out immediately before use. After adding Septrin 16 mg/80 mg per ml for Infusion to the infusion solution, shake thoroughly to ensure complete mixing. If visible turbidity or crystallisation appears at any time before or during an infusion, the mixture should be discarded.

It is recommended that Septrin16 mg/80 mg per ml for Infusion is diluted according to the following schedules:

-    One ampoule (5 ml) to 125 ml infusion solution.

-    Two ampoules (10 ml) to 250 ml infusion solution.

-    Three ampoules (15 ml) to 500 ml infusion solution.

Septrin 16 mg/80 mg per ml for Infusion is known to be compatible, when diluted as recommended above, with the following fluids:

-    Glucose Intravenous Infusion BP (5% w/v and 10% w/v).

-    Sodium Chloride Intravenous Infusion BP (0.9% w/v).

-    Sodium Chloride (0.18% w/v) and Glucose (4% w/v) Intravenous Infusion BP.

-    Dextran 70 Injection BP (6% w/v) in glucose (5% w/v) or normal saline.

-    Dextran 40 Injection BP (10% w/v) in glucose (5% w/v) or normal saline.

-    Ringer's Solution for Injection BPC 1959.

No other substance should be mixed with the infusion.

The duration of the infusion should be approximately one to one and a half hours, but this should be balanced against the fluid requirements of the patient.

When fluid restriction is necessary, Septrin 16 mg/80 mg per ml for Infusion may be administered at a higher concentration, 5 ml diluted with 75 ml of glucose 5% w/v in water. The resultant solution, whilst being clear to the naked eye, may on occasion exceed the BP limits set for particulate matter in large volume parenterals. The solution should be infused over a period not exceeding one hour. Discard any unused solution.

7. Marketing Authorisation Holder

Aspen Pharma Trading Limited 3016 Lake Drive,

Citywest Business Campus,

Dublin 24,

Ireland.

8    MARKETING AUTHORISATION NUMBER(S)

PL 39699/0044

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/10/2006

DATE OF REVISION OF THE TEXT

29/10/2014