Consumer medicine information

Bactrim 400/80

Sulfamethoxazole; Trimethoprim

BRAND INFORMATION

Brand name

Bactrim 400/80 Infusion Concentrate

Active ingredient

Sulfamethoxazole; Trimethoprim

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bactrim 400/80.

SUMMARY CMI

Bactrim® 400/80 (sulfamethoxazole 400 mg/5 mL and trimethoprim 80 mg/5 mL concentrate for solution for infusion)

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Bactrim® 400/80?

Bactrim® 400/80 contains the active ingredients sulfamethoxazole and trimethoprim. Bactrim® 400/80 is used to treat infections where the oral dosage form of the antibiotic is not appropriate.

For more information, see Section 1. Why am I using Bactrim® 400/80? In the full CMI.

2. What should I know before I use Bactrim® 400/80?

Do not use if you have ever had an allergic reaction to Bactrim® 400/80 or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breast-feeding.

For more information, see Section 2. What should I know before I use Bactrim® 400/80? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Bactrim® 400/80 and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Bactrim® 400/80?

Bactrim® 400/80 will be administered to you by a doctor, nurse or other trained professional.

More instructions can be found in Section 4. How do I use Bactrim® 400/80? in the full CMI.

5. What should I know while using Bactrim® 400/80?

Things you should do
  • Call your doctor straight away if you
    - Get severe diarrhoea, even if this occurs several weeks after treatment with Bactrim® 400/80 has stopped. Do not take diarrhoea medicine without first checking with your doctor.
    - Become pregnant whilst being treated, or within one month of being treated with Bactrim® 400/80. Bactrim® 400/80 is not recommended for use during pregnancy.
Things you should not do
  • Your doctor or nurse will advise if there are things you should be avoiding whilst being treated with Bactrim® 400/80.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Bactrim® 400/80 affects you.
  • Bactrim® 400/80 may cause dizziness in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Heavy alcohol use may increase the chance of experiencing a serious side effect.
Looking after your medicine
  • The hospital staff will store your medicine appropriately and also dispose of any unused Bactrim® 400/80.

For more information, see Section 5. What should I know while using Bactrim® 400/80? in the full CMI.

6. Are there any side effects?

Bactrim® 400/80 may cause side effects in some people, some of which include severe skin rashes, allergy, bleeding and bruising, low blood sugar and kidney impairment.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Bactrim® 400/80 (sulfamethoxazole 400 mg/5 mL and trimethoprim 80 mg/5 mL concentrate for solution for infusion) (BAC-trem)

Active ingredient(s): sulfamethoxazole, trimethoprim

Consumer Medicine Information (CMI)

This leaflet provides important information about using Bactrim® 400/80. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about Bactrim® 400/80.

Where to find information in this leaflet:

1. Why am I using Bactrim® 400/80?
2. What should I know before I use Bactrim® 400/80?
3. What if I am taking other medicines?
4. How do I use Bactrim® 400/80?
5. What should I know while using Bactrim® 400/80?
6. Are there any side effects?
7. Product details

1. Why am I using Bactrim® 400/80?

Bactrim® 400/80 contains the active ingredients sulfamethoxazole and trimethoprim. Sulfamethoxazole belongs to a group of medicines known as sulfonamides. Trimethoprim belongs to a group of medicines known as benzylpyrimidines. Together, both substances are more efficient than either one is alone.

Bactrim® 400/80 concentrate for solution for infusion is used to treat infections where the oral dosage form of the antibiotic is not appropriate.

2. What should I know before I use Bactrim® 400/80?

Warnings

Do not use Bactrim® 400/80 if you:

  • are allergic to trimethoprim
  • are allergic to sulfamethoxazole or drugs containing 'sulfa'.
  • are allergic to any of the ingredients listed at the end of this leaflet.
  • have severe liver disease
  • have abnormal cells in the blood
  • have severe kidney disease
  • have abnormal red blood cells (anaemias) associated with low levels of folic acid
  • a low platelet count with bleeding or bruising more easily than normal with previous use of trimethoprim and/or sulfonamides
  • are taking Dofetilide, used to treat heart arrhythmias

Always check the ingredients to make sure you can use this medicine.

Bactrim® 400/80 should not be given to premature babies or newborn babies (up to 8 weeks old).

Check with your doctor if you:

  • have any other medical conditions including
    - a deficiency of the enzyme glucose-a6-phosphate dehydrogenase (G6PD)
    - anaemia or other blood disorders
    - malnutrition
    - rheumatoid arthritis
    - kidney disease, or kidney transplant
    - liver disease (hepatitis)
    - HIV positive or AIDS
    - renal impairment or failure
    - phenylkenonuria
    - porphyria
    - thyroid disease
    - folate deficiency
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Bactrim® 400/80 is not recommended for use during pregnancy. If there is a need to consider Bactrim® 400/80 during your pregnancy, your doctor or pharmacist will discuss with you the benefits and risks of being given it. You may require a folic acid supplement to reduce the risk of harm to your unborn baby.

Talk to your doctor if you are breast-feeding or intend to breast-feed. Sulfamethoxazole/trimethoprim passes into breast milk and therefore there is a possibility that the breast-fed baby may be affected. If there is a need to consider Bactrim® 400/80 while you are breast-feeding, your doctor or pharmacist will discuss with you the benefits and risks of you being given it.

Use in elderly patients

The use of Bactrim® 400/80 in elderly patients carries an increased risk of severe adverse reactions. Your doctor or pharmacist will discuss with you the benefits and risks of Bactrim® 400/80.

Use to treat sore throat

Sulfonamides should generally not be used to treat a sore throat, specifically suspected or confirmed streptococcal infections.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Bactrim® 400/80 may interfere with each other. These include:

  • Methotrexate
  • Medicines that change the acidity of the urine (e.g. salts for cystitis)
  • Medicines used to prevent blood clots (blood thinners) such as warfarin
  • Phenylbutazone or indomethacin (medicines to reduce inflammation)
  • Phenytoin (a medicine for epilepsy)
  • Diuretic agents (fluid tablets), particularly thiazides
  • Hypoglycaemics (medicines to control blood sugar)
  • Digoxin, a medicine used to assist heart function
  • Ciclosporin, a medicine used to lower the immune system
  • Pyrimethamine, a medicine used in the treatment or prevention of malaria
  • Leucovorin (calcium folinate), antithyroid medicines (thionamides) used to treat overactive thyroid
  • Antithyroid medicines (thionamides) to treat overactive thyroid
  • Tricyclic antidepressants
  • Amiodarone used to treat heart arrhythmias
  • Paclitaxel a chemotherapy agent
  • Dapsone used to treat some skin conditions and leprosy
  • Dofetilide used to treat heart arrhythmias
  • Amantadine used to treat Parkinson's disease
  • Memantine used to treat Alzheimer's disease
  • Lamivudine used to treat human immunodeficiency virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS)

These medicines may be affected by Bactrim® 400/80 or may affect how well Bactrim® 400/80 works. You may need different amounts of your medicine, or you may need to take or use different medicines. Your doctor or pharmacist will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while you are being given this medicine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Bactrim® 400/80.

4. How do I use Bactrim® 400/80?

How much is given

  • Your doctor will decide what dose you will receive. The dose depends on your condition and other factors such as your age and weight.

When is it given

  • Bactrim® 400/80 is administered twice per day.

How is it given

  • Bactrim® 400/80 must always be diluted before use.
  • Bactrim® 400/80 is given as an intravenous infusion (i.e. a slow injection through a 'drip' into a vein) twice a day.
  • An infusion pump may be used to control the flow rate of the 'drip'.
  • This medicine should only be given by a doctor, nurse, or other trained person.

If a dose is missed

As Bactrim® 400/80 is given to you under the supervision of your doctor, it is very unlikely that a dose will be missed. Your doctor or pharmacist has information on how what to do if a dose has been missed.

If you are given too much Bactrim® 400/80

As Bactrim® 400/80 is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. Your doctor or pharmacist has information on how to recognize and treat an overdose.

Ask your doctor or pharmacist if you have any concerns.

The Poisons Information Centre can also provide advice for management of potential overdose (in Australia, call 13 11 26)

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Bactrim® 400/80?

Things you should do

Call your doctor straight away if you:

  • Get severe diarrhoea, even if this occurs several weeks after treatment with Bactrim® 400/80 has stopped. Do not take diarrhoea medicine without first checking with your doctor.
  • Become pregnant whilst being treated, or soon after being treated with Bactrim® 400/80. Bactrim® 400/80 is not recommended for use during pregnancy.

Things you should not do

  • Your doctor or nurse will advise if there are things you should be avoiding whilst being treated with Bactrim® 400/80.

Anticoagulant activity

  • Anticoagulant activity may be increased by concurrent treatment with Bactrim® 400/80. This interaction should be kept in mind, and the coagulation time should be monitored.

Use with sulfonylureas

  • Concomitant use of Bactrim® 400/80 with sulfonylureas may result in worsening of hypoglycaemia in occasional patients.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Bactrim® 400/80 affects you.

Bactrim® 400/80 may cause dizziness in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

Heavy alcohol use may increase the chance of experiencing a serious side effect.

Looking after your medicine

The hospital staff will store your medicine appropriately.

Getting rid of any unwanted medicine

The hospital staff will dispose of any unused Bactrim® 400/80.

They will also check that the expiry date has not passed.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
  • Pain or swelling at the injection site
  • Nausea or vomiting
  • Loss of appetite
  • Abdominal pain
  • Diarrhoea
  • Soreness of the mouth
  • Increased sensitivity of skin to the sun (sunburn)
  • Increased or decreased frequency of urination
  • Headache
  • Insomnia (difficulty sleeping)
  • Fatigue
  • Dizziness
  • Ringing in the ears
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Severe blisters and bleeding in the lips, eyes, mouth, nose or genitals
  • Itchy spots or red, painful rash or lumps under the skin, accompanied by a fast heartbeat, fever, weight loss and feeling unwell
  • Sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue, throat or other parts of the body, shortness of breath, wheezing or trouble breathing
  • Sore throat, fever or shortness of breath
  • Pain or aches in the joints
  • Fever, chills, cough, shortness of breath, phlegm and occasionally coughing blood
  • Pale skin
  • Unusual bleeding or bruising under the skin
  • Yellowing of the skin or whites of the eyes
  • Discolouration of urine or bowel motions
  • Renal stones
  • Low sugar (glucose) levels in the blood: sweating, weakness, hunger, dizziness, trembling, headache, flushing or paleness, numbness, having a fast, pounding heartbeat
  • Temporary paralysis or weakness of muscles
Call your doctor straight away.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Bactrim® 400/80 contains

Active ingredients
(ingredients that make the medicine work)		Sulfamethoxazole
Trimethoprim
Other ingredients
(inactive ingredients)		Monoethanolamine
Propylene glycol
Alcohol
Sodium hydroxide
Water for injections
Potential allergensDo not take this medicine if you are allergic to any of the active or other ingredients.

Do not take this medicine if you are allergic to any of these ingredients.

What Bactrim® 400/80 looks like

Bactrim® 400/80 is a clear and colourless to slightly yellowish liquid. It must always be diluted before use and should not be used if there are any crystals or cloudiness in the solution. Bactrim® 400/80 is contained in a small, glass ampoule.

Bactrim® 400/80 is supplied in a box of 10 x 5 mL ampoules (AUST R 367590).

Who distributes Bactrim® 400/80

Bactrim® 400/80 is supplied in Australia by:

Echo Therapeutics Pty Ltd
ABN 92628 298 699
Sydney, Australia
www.echotherapeutics.com.au

This leaflet was prepared in January 2024.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Bactrim 400/80 Infusion Concentrate

Active ingredient

Sulfamethoxazole; Trimethoprim

Schedule

S4

 

1 Name of Medicine

Sulfamethoxazole/trimethoprim.

2 Qualitative and Quantitative Composition

Bactrim 400/80: One ampoule of 5 mL contains 80 mg trimethoprim and 400 mg sulfamethoxazole (=480 mg sulfamethoxazole/trimethoprim). Contains 2050 mg propylene glycol, 500 mg ethanol abs. and 58.55 mg sodium hydroxide.
Sulfamethoxazole is a white or almost white, crystalline powder. It is practically insoluble in water, freely soluble in acetone, sparingly soluble in ethanol (96%). It dissolves in dilute solutions of sodium hydroxide and in dilute acids. Melting point is 169-172°C. Trimethoprim is a white or yellowish-white powder. It is very slightly soluble in water, slightly soluble in ethanol (96%). Melting point is 199-203°C.

Excipient(s) with known effect.

Alcohol 12.7% v/v.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrate for solution for infusion. The concentrate is clear and colourless to slightly yellowish.

4 Clinical Particulars

4.1 Therapeutic Indications

Parenteral administration of Bactrim is indicated where oral dosage is not desirable or practical, e.g. 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

Bactrim 400/80 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.
Bactrim 400/80 may be mixed only with the following solutions for infusion: 5% glucose, 10% glucose, 0.9% sodium chloride, 2.5% glucose/0.45% sodium chloride, Ringer's solution, dextran 70 (6%) in glucose (5%), 10% xylitol.
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 Bactrim 400/80 to 25 to 30 mL solution for infusion. 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.
Infusions containing Bactrim 400/80 must be administered to the patient within 6 hours of preparation. Bactrim 400/80 contains no antimicrobial agent and is for single use in one patient only. Discard any residue. Do not refrigerate prepared solution.

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.

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 Bactrim 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 pneumonitis is 20 mg/kg trimethoprim and 100 mg/kg sulfamethoxazole per 24 hours given in equally divided doses every 6 hours for 14 days.

Dosage in reduced renal function.

In patients with impaired renal function, the dosage and/or frequency of administration of sulfamethoxazole/trimethoprim needs to be modified.
The following dosage regimens have been published for the administration of sulfamethoxazole/trimethoprim tablets to patients with reduced kidney function. In view of the close similarity of plasma levels of trimethoprim and sulfamethoxazole when sulfamethoxazole/trimethoprim is given orally and intravenously, there is no reason to suppose that these regimens cannot be followed with Bactrim. See Table 1.

Duration of treatment.

Bactrim 400/80 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.

4.3 Contraindications

Sulfamethoxazole/trimethoprim is contraindicated in patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides and in patients showing marked hepatic damage, blood dyscrasias or with severe renal insufficiency and oliguria, where repeated measurements of the plasma concentrations cannot be performed. It should not be given to patients with known hypersensitivity to the active substance (trimethoprim, sulfonamides or cotrimoxazole) or to one of the excipients listed in Section 6.1 List of Excipients, or with documented megaloblastic anaemia secondary to folate deficiency.
Bactrim must not be given in combination with dofetilide (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
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.
Use of Bactrim for treatment of streptococcal pharyngitis is contraindicated (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Sulfamethoxazole/trimethoprim should only be used for the prevention or treatment of infections caused by micro-organisms that are proven to be sensitive to sulfamethoxazole/trimethoprim or for which there is strong evidence that they are sensitive. In the absence of such data, local epidemiological data and susceptibility patterns may help in the choice of an appropriate antibiotic. In order to exclude resistance, especially if infections are (probably) caused by partially sensitive organisms, the isolate should be tested for susceptibility to sulfamethoxazole/trimethoprim.

Hypersensitivity and allergic reactions.

Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment. 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, the patient should be re-evaluated and discontinuation of sulfamethoxazole/trimethoprim therapy considered.

Life-threatening adverse reactions.

Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias, acute and delayed lung injury, hypersensitivity of the respiratory tract, and circulatory shock.

Severe cutaneous adverse reactions.

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalised exanthematous pustulosis (AGEP) and drug reaction with eosinophilia with systemic symptoms (DRESS) have been reported with the use of sulfamethoxazole/trimethoprim.
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, TEN (e.g. progressive skin rash often with blisters or mucosal lesions), AGEP or DRESS (e.g. fever, eosinophilia) are present, Bactrim 400/80 treatment should be discontinued immediately (see Section 4.8 Adverse Effects (Undesirable Effects)) and an alternative treatment should be considered.
The best results in managing SJS, TEN or DRESS 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, TEN or DRESS with the use of Bactrim 400/80, Bactrim 400/80 must not be re-started in this patient at any time.
At the start of treatment, the occurrence of a generalised febrile erythema associated with pustules, should raise the suspicion of AGEP (see Section 4.8 Adverse Effects (Undesirable Effects)); it requires cessation of treatment and contraindicates any new administration of Bactrim alone or in combination with other drugs.

Haemophagocytic lymphohistiocytosis (HLH).

Cases of HLH have been reported very rarely in patients treated with sulfamethoxazole/trimethoprim. HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of an excessive systemic inflammation (e.g. fever, hepatosplenomegaly, hypertriglyceridaemia, hypofibrinogenaemia, high serum ferritin, cytopenias and haemophagocytosis). Patients who develop early manifestations of pathologic immune activation should be evaluated immediately. If diagnosis of HLH is established, sulfamethoxazole/trimethoprim treatment should be discontinued.

Respiratory tract.

Cough, shortness of breath, and pulmonary infiltrates potentially representing hypersensitivity reactions of the respiratory tract have been reported in association with trimethoprim-sulfamethoxazole treatment.
Other severe pulmonary adverse reactions occurring within days to week of trimethoprim-sulfamethoxazole initiation and resulting in prolonged respiratory failure requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO), lung transplantation or death have also been reported in patients and otherwise healthy individuals treated with trimethoprim-sulfamethoxazole products.

Circulatory shock.

Circulatory shock with fever, severe hypotension, and confusion requiring intravenous fluid resuscitation and vasopressors has occurred within minutes to hours of re-challenge with trimethoprim-sulfamethoxazole in patients with history of recent (days to weeks) exposure to sulfamethoxazole-trimethoprim.
Acute respiratory failure including acute eosinophilic pneumonia has been reported in healthy adolescents with sulfamethoxazole/trimethoprim treatment.
Sulfamethoxazole/trimethoprim should be discontinued immediately as soon as there are symptoms of a skin rash (e.g. exanthema) or other serious side effects. Clinical signs such as rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura or jaundice may be early indications of serious reactions.

Thrombocytopenia.

Sulfamethoxazole/trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole/trimethoprim.

Streptococcal infections and rheumatic fever.

The sulfonamides should not be used for the treatment of group A beta-haemolytic streptococcal infections (see Section 4.3 Contraindications). In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.

Use in treatment of "Pneumocystis jirovecii" pneumonitis in patients with acquired immunodeficiency syndrome (AIDS).

Because of their unique immune dysfunction, AIDS patients may not tolerate or respond to sulfamethoxazole/trimethoprim in the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, neutropenia, thrombocytopenia, raised liver enzymes and leucopenia necessitating cessation of therapy, with sulfamethoxazole/trimethoprim therapy in AIDS 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-AIDS patients. Such adverse effects have occurred in up to 80% of AIDS 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 of Pneumocystis jirovecii pneumonia compared with those receiving sulfamethoxazole/trimethoprim for treatment of the disease.

Adjunctive treatment with leucovorin for Pneumocystis jirovecii pneumonia.

Treatment failure and excess mortality were observed when sulfamethoxazole/trimethoprim was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jirovecii pneumonia in a randomized placebo-controlled trial. Co-administration of sulfamethoxazole/trimethoprim and leucovorin during treatment of Pneumocystis jirovecii pneumonia should be avoided.

Use in glucose-6-phosphate dehydrogenase deficiency.

In individuals with glucose-6-phosphate dehydrogenase deficiency, haemolysis may occur. This is frequently dose-related.

Clostridioides difficile associated diarrhoea (CDAD).

Clostridioides difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. 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 antibiotic therapy).
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against C. difficile should be considered. Fluids, electrolytes and protein replacement, antibiotic treatment of C. difficile, and surgical evaluation should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used.

Hypoglycaemia.

Cases of hypoglycaemia in non-diabetic patients treated with sulfamethoxazole/trimethoprim have been reported, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of sulfamethoxazole/trimethoprim are particularly at risk.

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, or in 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 Interactions with Other Medicines and Other Forms of Interactions). Severe and symptomatic hyponatremia can occur in patients receiving sulfamethoxazole/trimethoprim, particularly for the treatment of P. jirovecii pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.
Patients who are "slow acetylators" may be more prone to idiosyncratic reactions to sulfonamides.

Laboratory tests.

Complete blood counts should be done frequently in patients receiving sulfamethoxazole/trimethoprim; if a significant reduction in the count of any formed blood element is noted, sulfamethoxazole/trimethoprim should be discontinued.

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 and barbiturates. Folic acid may be 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, Bactrim administration should be ceased; leucovorin may be administered.

Phenylalanine metabolism.

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

Porphyria and hypothyroidism.

As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction.

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 and urinary output 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.

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, e.g. impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, or generalised bone marrow suppression (see Section 4.8 Adverse Effects (Undesirable Effects)) or a specific decrease in platelets (with or without purpura), and hyperkalaemia are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant sulfamethoxazole/trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored. Haematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimise risks of undesired reactions (see Section 4.2 Dose and Method of Administration). The trimethoprim component of sulfamethoxazole/trimethoprim may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of sulfamethoxazole/trimethoprim treatment is recommended to help lower potassium serum levels.
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.

Paediatric use.

See Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications.

Effects on laboratory tests.

Two laboratory procedures, namely the Lactobacillus casei serum folate assay and the L. leishmanii serum vitamin B12 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.

Other.

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

Methotrexate.

Sulfonamides such as sulfamethoxazole may displace methotrexate from protein binding sites and can compete with the renal transport of methotrexate, 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.

Warfarin/anticoagulants.

Anticoagulant activity may be increased by concurrent treatment with sulfamethoxazole/trimethoprim. It has been reported that sulfamethoxazole/trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when sulfamethoxazole/trimethoprim is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.

Phenytoin.

Increased effects and side effects of phenytoin (folate deficiencies) could occur when sulfamethoxazole/trimethoprim is given concurrently. Sulfamethoxazole/trimethoprim may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). Oral sulfamethoxazole/trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.

Sulfonylureas.

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.

Ciclosporin.

Deterioration in renal function in patients with renal transplants. There have been reports of marked but reversible nephrotoxicity with co-administration of sulfamethoxazole/trimethoprim and ciclosporin in renal transplant recipients.

Amiodarone.

Sulfamethoxazole/trimethoprim may increase the plasma concentration of amiodarone. Therefore, concomitant use of Bactrim with amiodarone is not recommended.

Paclitaxel.

Sulfamethoxazole/trimethoprim may increase the plasma concentration of paclitaxel. Therefore, caution is advised for concomitant administration of paclitaxel and Bactrim.

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.

Dapsone.

Both dapsone and sulfamethoxazole/trimethoprim may cause methemoglobinemia and the effect of dapsone may be further strengthened by the pharmacokinetic and pharmacodynamic interaction with sulfamethoxazole/trimethoprim. If possible, alternative therapies should be considered. If sulfamethoxazole/trimethoprim and dapsone are used concomitantly, caution should be exercised and careful monitoring on methemoglobinemia is recommended, especially for high risk patients with significant comorbidities or in patients receiving a high dose of one of both agents.

Digoxin.

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

Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, potassium sparing diuretics, prednisolone.

Due to the potassium sparing effects of 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 Special Warnings and Precautions for Use). In the literature, two cases of hyperkalaemia in elderly patients have been reported after concomitant intake of sulfamethoxazole/trimethoprim and an angiotensin converting enzyme inhibitor.

Tricyclic antidepressants.

The efficacy of tricyclic antidepressants can decrease when co-administered with sulfamethoxazole/trimethoprim.

Increased sulfamethoxazole blood levels.

May occur in patients who are also receiving urinary acidifiers, oral anticoagulants, phenylbutazone, oxyphenbutazone and indomethacin.

Cross sensitisation.

May exist between sulfamethoxazole/trimethoprim and some antithyroid agents, diuretics (acetazolamide and the thiazides) and oral hypoglycaemic drugs.
Trimethoprim is an inhibitor of CYP2C8 as well as an OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Caution is recommended when Sulfamethoxazole/trimethoprim is coadministered with drugs that are substrates of CYP2C8 and 2C9 or OCT2. Sulfamethoxazole/trimethoprim potentiates the effect of oral hypoglycaemics that are metabolised by CYP2C8 (e.g. pioglitazone, repaglinide, and rosiglitazone) or CYP2C9 (e.g. glipizide and glyburide) or eliminated renally via OCT2 (e.g. metformin). Additional monitoring of blood glucose may be warranted.

Dofetilide.

Concurrent administration is contraindicated (see Section 4.3 Contraindications). Elevated plasma concentrations of dofetilide have been reported following concurrent administration of trimethoprim and dofetilide. Increased plasma concentrations of dofetilide may cause serious ventricular arrhythmias associated with QT interval prolongation, including torsade de pointes.
In the literature, some cases of toxic delirium and myoclonus have been reported after concomitant intake of sulfamethoxazole/trimethoprim and amantadine (an OCT2 substrate). Cases of interactions with other OCT2 substrates, memantine, metformin, dofetilide, amantadine and lamivudine have also been reported.

Others.

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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(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.
If sulfamethoxazole/trimethoprim is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus.
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. Because trimethoprim and sulfamethoxazole may interfere with folic acid metabolism, Sulfamethoxazole/trimethoprim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Section 4.4 Special Warnings and Precautions for Use).
Trimethoprim and sulfamethoxazole, alone and in combination, have produced teratogenic effects (cleft palate) in some studies in rats receiving dosages exceeding the usual human dosage.

Human data.

While there are no large prospective, well-controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to sulfamethoxazole/trimethoprim with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalisability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons.
Alternatively, other epidemiologic studies did not detect statistically significant associations between sulfamethoxazole/trimethoprim exposure and specific malformations.
 Both trimethoprim and sulfamethoxazole are excreted in breast milk at concentrations comparable or somewhat lower than those in the blood. Although the quantity of sulfamethoxazole/trimethoprim ingested by a breast-fed infant is small, caution should be exercised when sulfamethoxazole/trimethoprim is administered to a nursing woman, especially when breastfeeding jaundiced, ill, stressed, or premature infants because of the potential risk of bilirubin displacement and kernicterus, and it is recommended that the age of the infant be considered and the possible risks be balanced against the expected therapeutic effect.
An increased risk of hyperbilirubinemia should be considered in premature neonates and children with glucose-6-phosphate dehydrogenase deficiency.

4.7 Effects on Ability to Drive and Use Machines

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 Adverse Effects (Undesirable Effects)

The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria).
Fatalities, associated with the administration of sulfonamides although rare, have occurred due to severe reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias, hypersensitivity of the respiratory tract, acute and delayed lung injury, and circulatory shock (see Section 4.4 Special Warnings and Precautions for Use). Treatment with sulfamethoxazole/trimethoprim must be stopped immediately as soon as there are symptoms of skin rash (e.g. exanthema) or other serious side effects. 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 to 7% of patients treated in the published literature. In general, the adverse reactions correspond to those of a sulfonamide of moderately low toxicity.

Tabulated list of adverse reactions.

The following convention has been used for the classification of adverse reactions in terms of frequency: very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1,000 and < 1/100; rare ≥ 1/10,000 and < 1/1000; very rare < 1/10,000; not known - cannot be estimated from the available data. See Table 2.

Description of selected adverse reactions.

Gastrointestinal disorders.

Nausea and vomiting are the most frequent gastrointestinal reactions to sulfamethoxazole/trimethoprim, but glossitis, stomatitis, abdominal pain, pancreatitis, pseudomembranous colitis and diarrhoea have also been reported.

Blood and lymphatic system disorders.

Haematological changes have been observed in some patients, particularly the elderly. The 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, hypoprothrombinaemia, aplastic and haemolytic anaemia, purpura, agranulocytosis and bone marrow depression have been observed less frequently. Haematological toxicity may occur with increased frequency in folate depleted patients including geriatric, malnourished, alcoholic, pregnant or debilitated patients; in patients receiving anti-folates (e.g. 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 (e.g. longer than 6 months). In geriatric patients receiving some diuretics (principally thiazides) and sulfamethoxazole/trimethoprim concomitantly, an increased incidence of thrombocytopenia with purpura has been reported. The risk of leucopenia, neutropenia and thrombocytopenia also appear to be increased in patients with AIDS.

Congenital disorders and pregnancy, puerperium, and perinatal conditions.

Spontaneous abortion have been observed.

Immune system disorders.

Several cases of Stevens-Johnson syndrome (erythema multiforme bullosa) and toxic epidermal necrolysis (TEN) 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 angioedema, serum sickness-like syndrome, generalised allergic reactions, generalised skin eruptions, anaphylaxis, erythema multiforme, drug fever, chills, Henoch-Schonlein purpura, pruritus, urticaria, periorbital oedema, corneal ring infiltrates, conjunctival and scleral redness and oedema, and photosensitivity. In addition, periarteritis nodosa and a positive lupus erythematous phenomenon, and systemic lupus erythematosus have been reported.
Mild to moderate rashes, when they occur, usually appear within 7 to 14 days after initiation of sulfamethoxazole/trimethoprim. Rashes are generally erythematous, maculopapular, morbilliform, and/or pruritic. Generalised pustular dermatosis and fixed drug eruption have also been reported. Patients with AIDS appear to be at particular risk of developing rash (usually diffuse, erythematous and maculopapular) during sulfamethoxazole/trimethoprim therapy.

Hepatobiliary disorders.

Hepatitis, hepatic changes (as indicated by abnormal elevations in alkaline phosphatase and serum transaminase levels) including cholestatic jaundice and 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.

Renal and urinary disorders.

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 nephrotoxicity in association with ciclosporin have been reported. Crystalluria and stone formation have occurred in patients receiving sulfamethoxazole/trimethoprim. Cases of urolithiasis have been reported in patients treated with co-trimoxazole. Renal stones formed by N-acetylsulfamethoxazole crystals aggregation (either 100% or partial) have been described. A causal association is defined specifically for urolithiasis composed from Bactrim metabolites (either 100% or partial), when specific patient risk factors, like crystalluria or reduced urinary output, are met.

Metabolism and nutrition disorders.

Anorexia.
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 of patients. Even treatment with recommended doses may 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 Special Warnings and Precautions for Use).

Nervous system disorders.

Aseptic meningitis, seizures, peripheral neuritis, ataxia, vertigo, tinnitus, headache. Tremor and other neurologic manifestations (e.g. ataxia, ankle clonus, apathy) developed during sulfamethoxazole/trimethoprim therapy in several patients with AIDS; although such manifestations have also been associated with the underlying disease process, they resolved in these patients within 2 to 3 days after discontinuing the drug.

Psychiatric disorders.

Adverse nervous system effects of sulfamethoxazole/trimethoprim include, insomnia, apathy, nervousness, mental depression and hallucinations.

Endocrine disorders.

The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycaemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycaemia has occurred rarely in patients receiving sulfonamides.

Infections and infestations.

Fungal infections (such as candidiasis) were reported.

Musculoskeletal and connective tissue disorders.

Arthralgia, myalgia, muscle weakness. Cases of rhabdomyolysis have been reported with sulfamethoxazole/trimethoprim, mainly in AIDS patients.

Respiratory, thoracic and mediastinal disorders.

Cough, shortness of breath, pulmonary infiltrates, pulmonary vasculitis, acute eosinophilic pneumonia, acute and delayed lung injury, interstitial lung disease, and acute respiratory failure. Epistaxis has been reported rarely.

General disorders and administration site conditions.

Weakness, fatigue, pain, local irritation, inflammation, and thrombophlebitis may occasionally occur with intravenous sulfamethoxazole/trimethoprim, especially if extravasation of the drug occurs.

Skin and subcutaneous tissue disorders.

Acute febrile neutrophilic dermatosis has been reported with certain antibiotics. Alopecia has been reported rarely.
Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported to be life-threatening. Acute generalised exanthematous pustulosis (AGEP) has been reported with certain antibiotics. See Section 4.4 Special Warnings and Precautions for Use.

Vascular disorders.

Hypotension.

Eye disorders.

Vision problems have been reported rarely. Uveitis and retinal vasculitis have been reported.

Post-marketing experience.

The following adverse reactions have been identified during post-approval use of sulfamethoxazole/trimethoprim. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: thrombotic thrombocytopenia purpura; idiopathic thrombocytopenic purpura; QT prolongation resulting in ventricular tachycardia and torsade de pointes.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Acute.

Symptoms.

Signs and symptoms of overdosage with include anorexia, diarrhoea, colic, nausea, vomiting, dizziness, headache, mental and visual disturbances, drowsiness, and unconsciousness. Pyrexia, haematuria, anuria and crystalluria may be noted. Bone marrow depression (manifested as thrombocytopaenia or leucopaenia) and blood dyscrasias and jaundice are potential late manifestations of overdosage. Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion, and bone marrow depression.

Treatment.

Stop therapy. Treatment of overdose is supportive and symptomatic care. Force fluids orally or parenterally if renal function is normal. In extreme overdosage in patients with impaired renal function, consider haemodialysis (peritoneal dialysis is ineffective) which is moderately effective in removing sulfamethoxazole and trimethoprim, monitoring of blood count and electrolytes. Acidification of the urine will increase renal elimination of trimethoprim. The patient should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is ineffective.

Chronic.

Use of sulfamethoxazole/trimethoprim at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia, and/or megaloblastic anemia. If signs of bone marrow depression occur, the patient should be given leucovorin.
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 information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

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 and gram-positive organisms, e.g. E. coli, Neisseria, Salmonella, Klebsiella, Enterobacter, Shigella, Vibrio cholerae, Bordetella pertussis, Streptococcus, Staphylococcus, Pneumococcus, Haemophilus influenzae and Proteus.
Sulfamethoxazole/trimethoprim is also active against the protozoan Pneumocystis jirovecii. However, Mycobacterium tuberculosis, Treponema pallidum, Mycoplasma and Pseudomonas aeruginosa are frequently resistant to sulfamethoxazole/trimethoprim.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Concentrations of at least 0.5 microgram/mL trimethoprim and 20 microgram/mL sulfamethoxazole are reached within 30 minutes after the start of an infusion and are maintained for at least 12 hours. Mean peak steady state serum concentrations of approximately 9 and 105 microgram/mL of trimethoprim and sulfamethoxazole, respectively, are reached after intravenous (IV) infusion of 160 mg trimethoprim and 800 mg 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 and 70 microgram/mL of sulfamethoxazole. The administration of a trimethoprim/sulfamethoxazole ratio of 1:5 achieves trimethoprim/sulfamethoxazole concentrations in the blood of about 1:20.

Distribution.

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.

Metabolism.

Sulfamethoxazole/trimethoprim is metabolised in the liver. Trimethoprim is metabolised to oxide and hydroxylated metabolites, while sulfamethoxazole is acetylated and conjugated with glucuronic acid.

Excretion.

Sulfamethoxazole/trimethoprim is rapidly excreted in the urine.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Monoethanolamine, propylene glycol, ethanol absolute, sodium hydroxide, water for injection.

6.2 Incompatibilities

Bactrim 400/80 has been found to be stable for 6 hours at room temperature under normal daylight conditions when admixed with the following solutions in a concentration of 0.03 mL/mL and 0.04 mL/mL: 5% glucose; 10% glucose; 0.9% sodium chloride; 2.5% glucose/0.45% sodium chloride; Ringer's solution; dextran 70 (6%) in glucose (5%); 10% xylitol.
No other agent should be added to or mixed with the infusion.
Do not add any products to Bactrim 400/80 other than the infusion fluids listed above, and especially no products that lower the pH to less than 8 as this may result in precipitation.
Levulose 5%, Hartmann solution and sodium bicarbonate 1.4% solution must not be used to dilute Bactrim 400/80.
The solution for infusion containing Bactrim 400/80 must be administered to the patient within 6 hours of preparation.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Do not refrigerate.
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

Bactrim 400/80 is supplied as a 5 mL ampoule (made of type 1 glass) containing 400 mg sulfamethoxazole and 80 mg trimethoprim in packs of 10 ampoules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Sulfamethoxazole.


Chemical name: 3-(4-aminobenzenesulfonamido)-5-methylisoxazole.
Molecular formula: C10H11N3O3S.
Molecular weight: 253.28.

CAS number.

723-46-6.

Chemical structure.

Trimethoprim.


Chemical name: 2, 4-diamino-5-(3, 4, 5-trimethoxybenzyl) pyrimidine.
Molecular formula: C14H18N4O3.
Molecular weight: 290.3.

CAS number.

738-70-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes