Consumer medicine information

Septrin Sugar-Free Paediatric Suspension

Trimethoprim; Sulfamethoxazole

BRAND INFORMATION

Brand name

Septrin Sugar Free Oral Liquid

Active ingredient

Trimethoprim; Sulfamethoxazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Septrin Sugar-Free Paediatric Suspension.

SUMMARY CMI

SEPTRIN Sugar-Free Paediatric Suspension

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 SEPTRIN?

SEPTRIN contains the active ingredients trimethoprim and sulfamethoxazole. SEPTRIN is used for the treatment of a variety of bacterial infections, including bronchitis and infections of the ear, sinus, kidney, bladder, stomach, bowel, skin and wounds.

For more information, see Section 1. Why am I using SEPTRIN? in the full CMI.

2. What should I know before I use SEPTRIN?

Do not use if you have ever had an allergic reaction to trimethoprim and sulfamethoxazole 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 breastfeeding.

For more information, see Section 2. What should I know before I use SEPTRIN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SEPTRIN 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 SEPTRIN?

  • Take SEPTRIN as directed by your doctor or pharmacist
  • Follow the instructions provided and use SEPTRIN until your doctor tells you to stop.

More instructions can be found in Section 4. How do I use SEPTRIN? in the full CMI.

5. What should I know while using SEPTRIN?

Things you should do
  • It is important that you drink plenty of fluids (water) while you are taking SEPTRIN.
  • Tell your doctor that you are taking SEPTRIN before you have any blood tests.
Things you should not do
  • Do not stop using this medicine suddenly just because you feel better.
  • It is important that you take the full course of SEPTRIN prescribed by your doctor. This will reduce the risk of your infection recurring.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how SEPTRIN affects you
  • Your skin may burn more easily while you are taking SEPTRIN. If outdoors, wear protective clothing or use a SPF 30+ sunscreen.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep SEPTRIN Sugar-Free Suspension in a cool dry place where the temperature stays below 25°C.
  • Protect the suspension from light.
  • Keep your SEPTRIN in the container it was supplied with
  • Heat and dampness may affect this medicine
  • Keep it where young children cannot reach it.

For more information, see Section 5. What should I know while using SEPTRIN? in the full CMI.

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

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

SEPTRIN Sugar-Free Paediatric Suspension

Active ingredient(s): trimethoprim and sulfamethoxazole

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using SEPTRIN?

SEPTRIN contains the active ingredients trimethoprim and sulfamethoxazole. SEPTRIN is used for the treatment of a variety of bacterial infections, including bronchitis and infections of the ear, sinus, kidney, bladder, stomach, bowel, skin and wounds.

Trimethoprim and sulfamethoxazole (the active ingredients in SEPTRIN) belong to a group of medicines called "anti-infectives". They work in slightly different ways to stop the growth of bacteria causing the infection.

If you have any questions about why you are taking SEPTRIN, ask your doctor or pharmacist. Your doctor may have prescribed it for another reason.

There is no evidence that this medicine is addictive.

SEPTRIN is only available with a doctor's prescription.

2. What should I know before I use SEPTRIN?

Warnings

Do not use SEPTRIN if:

  • you are allergic to Trimethoprim, Sulfamethoxazole, any other sulfonamide (sulfur) antibiotic or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • are allergic to trimethoprim, sulfamethoxazole or any other ingredient listed at the end of this information.
  • any other sulphonamide type antibiotics, any diuretics (medicines that increase the volume of your urine), or medicines for diabetes or an overactive thyroid gland.
  • have any other medical conditions including:
    - Acute porphyria
    - Severe atopy
    - Any type of liver, kidney or bladder complaint or disease (e.g. hepatitis)
    - History of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulphonamides
    - Documented megaloblastic anemia due to folate deficiency or blood dyscrasia
    - Any type of blood disorder (including porphyria and glucose-6-phosphate dehydrogenase deficiency)
    - At risk of hyperkalaemia and hyponatraemia
    - Haemophagocytic lymphohistiocytosis
    - Asthma or an allergic disorder
    - Underweight or malnourished
    - Phenylketonuria
    - Gastrointestinal tract infection
    - Alcoholism
    - Suffer from rheumatoid arthritis
    - Being treated for epilepsy (fits)
    - Take any medicines for any other condition
    - Have been diagnosed with AIDS

People with AIDS may not tolerate or respond to SEPTRIN in the same manner as someone who does not have AIDS. There may be an increase in the number and severity of side effects.

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.

If you become pregnant, while taking SEPTRIN, tell your doctor straight away. Administration of SEPTRIN should be avoided in pregnancy especially in the first trimester, unless clearly necessary as Trimethoprim and sulfamethoxazole cross the placenta and their safety in human pregnancy has not been established.

Administration of SEPTRIN should be avoided in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilirubinaemia

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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.

If you are taking any medicines, including:

  • Any malaria medicines (eg. pyrimethamine)
  • Any diabetes medicines suchas repaglinide, rosiglitazone, pioglitazone, glibenclamide, gliclazide, glipizide, chlorpropamide and tolbutamide
  • Any diuretics (diuretics)
  • Any epilepsy (fits) medicines (eg. phenytoin, primidone and some barbiturates)
  • Any medicines used to treat infections such as rifampicin, dapsone and polymyxin
  • Zidovudine, a medicine to treat HIV infection
  • Ciclosporin, a medicine used to prevent organ transplant rejections or to treat certain problems with the immune system
  • Warfarin, acenocoumarol, phenprocoumon, medicines used to thin the blood
  • Medicines used to treat some heart conditions such as digoxin and amiodarone
  • Amantadine, a medicine commonly used to treat the influenza virus and Parkinson's disease
  • Memantine, a medicine used to treat Parkinson's disease
  • Lamivudine, an antiretroviral medicine used to treat HIV/AIDS
  • Urinary acidifiers (for kidney conditions) oral contraceptives (‘the pill’)
  • Sulfinpyrazone, a medicine used to treat gout
  • Salicylates, medicines to treat conditions such as psoriasis or warts
  • Medicines used to treat cancer such as paclitaxel, mercaptopurine and methotrexate
  • Clozapine, a medicine used to treat schizophrenia
  • Medicines used to treat overactive thyroid conditions
  • Medicines used to treat depression such as imipramine, clomipramine, amitriptyline, dosulepin (dothiepin), doxepin, nortriptyline and trimipramine
  • Immunosuppressant medicines such as azathioprine and methotrexate
  • Medicines used to treat high blood pressure as well as a variety of heart and kidney conditions such as captopril, enalapril, lisinopril, fosinopril, perindopril, quinapril, ramipril, trandolapril, valsartan, telmisartan, irbesartan, candesartan, eprosartan, losartan, dofetilide and olmesartan
  • Procainamide
  • Folinic acid
  • Medicines that can cause hyperkalaemia, for example ACE inhibitors, angiotensin receptor blockers and potassium-sparing diuretics such as spironolactone.
  • Sulphonylurea hypoglycemic agents.
  • Trimethoprim is an inhibitor of cytochrome P450 2C8 enzyme and may interact with other drugs that are primarily metabolized by the 2C8 isoform. Sulfamethoxazole is an inhibitor of cytochrome P450 2C9 and may interact with other drugs that are primarily metabolized by the 2C9 isoform.

These medicines may be affected by SEPTRIN or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

If you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

Your doctor will have a complete list of the medicines that may cause problems when taken with SEPTRIN.

SEPTRIN and very young children

SEPTRIN should not be used in premature babies or in infants during the first 2 months of life.

SEPTRIN and the elderly

The use of SEPTRIN in elderly patients, particularly those with a liver or kidney disease or those taking certain other medicines such as diuretics (thiazides), carries an increased risk of severe adverse reactions.

In addition, the appearance of skin rashes, particularly in elderly patients, warrants the immediate removal of treatment.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SEPTRIN.

4. How do I use SEPTRIN?

How much to take

  • Take SEPTRIN as directed by your doctor or pharmacist
  • Follow the instructions provided and use SEPTRIN until your doctor tells you to stop.

When to take SEPTRIN

  • The dose of SEPTRIN Sugar-Free Paediatric Suspension for children under 12 years old depends on your child's weight and age. Your doctor or pharmacist will be able to tell you how much your child should be given.
  • Depending on the type of infection, and your overall health, your doctor may prescribe a different dose of SEPTRIN.
  • Always take the full course of SEPTRIN prescribed by your doctor.

How to take SEPTRIN

  • SEPTRIN Sugar-Free Paediatric Suspension should be shaken before use. The correct amount of the suspension should be measured before being given by mouth.

If you forget to use SEPTRIN

SEPTRIN should be used regularly at the same time each day. If you miss your dose at the usual time, skip the dose that you have missed and take your next dose when you are meant to.

Otherwise take the dose that you have missed as soon as you remember, then go back to your normal schedule.

If you have forgotten to take more than one dose, contact your doctor or pharmacist.

Do not take a double dose to make up for the dose that you have missed.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

Do not take a double dose to make up for the dose you missed.

If you use too much SEPTRIN

If you think that you have used too much SEPTRIN, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If too much SEPTRIN has been taken signs and symptoms may include nausea, vomiting, dizziness, headache, depression and confusion. It is also possible that you will feel drowsy and you may lose consciousness.

5. What should I know while using SEPTRIN?

Things you should do

It is important that you drink plenty of fluids (water) while you are taking SEPTRIN.

Tell your doctor that you are taking SEPTRIN before you have any blood tests.

If you are taking SEPTRIN over a long period, or you have kidney problems, your doctor may ask you to undergo regular blood and urine tests.

Your doctor or pharmacist will be able to tell you whether there are any other special instructions while you are taking SEPTRIN.

If you become pregnant while taking SEPTRIN, tell your doctor.

Call your doctor straight away if you:

  • get severe diarrhoea, even if it occurs several weeks after stopping SEPTRIN.

Remind any doctor, dentist or pharmacist you visit that you are using SEPTRIN. Do not take any diarrhoea medicine without checking with your doctor.

Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care.

Things you should not do

  • Do not stop using this medicine suddenly just because you feel better.
  • It is important that you take the full course of SEPTRIN prescribed by your doctor. This will reduce the risk of your infection recurring.
  • Your doctor will advise you when to stop taking SEPTRIN.

If you are unsure whether you should stop taking SEPTRIN, talk to your doctor or pharmacist.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SEPTRIN affects you.

Sometimes use of this medicine allows other bacteria and fungi which are not sensitive to SEPTRIN grow. If other infections such as thrush occur while you are taking SEPTRIN tell your doctor.

Your skin may burn more easily while you are taking SEPTRIN. If outdoors, wear protective clothing or use a SPF 30+ sunscreen.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep SEPTRIN Sugar-Free Suspension in a cool dry place where the temperature stays below 25°C.
  • Protect the suspension from light.
  • Keep your SEPTRIN in the container it was supplied with

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car on hot days or on window sills.

Heat and dampness may affect this medicine

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor advises you to stop taking SEPTRIN, ask your pharmacist what to do with any SEPTRIN that you may have left.

Do not take SEPTRIN:

  • after the expiry date printed on the pack or bottle.The medicine may have no effect if you take it after the expiry date.
  • if the packaging appears to have been tampered with.
  • to treat any other conditions unless advised by your doctor.
  • Do not give SEPTRIN to anyone else, even if their symptoms seem similar to yours.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

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.

Stop taking SEPTRIN and tell your doctor immediately if you notice, or experience, any of the following (you may need urgent 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.

Less serious side effects

Less serious side effectsWhat to do
  • Nausea
  • Dry mouth
  • Vomiting
  • Sores
  • Peeling of skin
  • Diarrhoea or other abdominal (gut)
  • Stomach discomfort
  • Inflammation of the mouth or tongue
  • Weakness
  • Fatigue
  • Body aches
  • Insomnia
  • Vision troubles
  • Alopecia
  • Epistaxis
  • Edema
  • QT prolongation
  • Pyrosis
  • Gastric intolerance
  • Gastritis or gastroenteritis
  • Dyspepsia emesis
  • Constipation
  • Flatulence
  • Tooth and/or tongue discoloration
  • Kidney changes
  • Hematuria, urgency, and dysuria, hypoprothrombinemia
  • Tremor.
  • Monilial overgrowth is common
  • Oral thrush (white, furry sore tongue and mouth)
  • Vaginal thrush (sore and itchy vagina, vaginal discharge).
  • Pseudomembranous enterocolitis
  • pancreatitis
Speak to your doctor if you have any of these less serious side effects and they worry you. These side effects are not usually serious or long lasting.
For thrush, your doctor will need to treat the thrush infection separately.

Serious side effects

Serious side effectsWhat to do
  • Any form of skin rash.
  • The rash may indicate that you are allergic to SEPTRIN. In very rare circumstances, patients have died from complications that may arise from certain severe allergic reactions (Stevens-Johnson syndrome
  • (SJS), toxic epidermal necrolysis (TEN) and drug reaction with
  • eosinophilia and systemic symptoms (DRESS)). Your doctor will know what action to take if you develop a severe reaction.
  • Severe fever, chills, sore throat, joint pains, cough or bruising.
  • Difficulty breathing or chest pains.
  • Severe, persistent diarrhoea. This is particularly important if there is any blood or mucus present. It is possible for this reaction to only become apparent several weeks after taking SEPTRIN.
  • Jaundice (yellowing of the skin), which is related to the function of your liver.
  • Severe persistent headache.
  • Discolouration of urine.
  • Acute generalised exanthematous pustulosis (AGEP)
  • Cholestatic jaundice and hepatic necrosis may be fatal.
  • Haematological changes
  • Toxicoderma
  • Exfoliative dermatitis
  • Serum sickness
  • Generalized skin eruptions
  • Pruritus
  • Urticaria
  • Anaphylactoid reactions (sweating and collapse)
  • Pins and needles in the hands and feet
  • Ringing in the ears
  • Loss of appetite
  • Metabolism and nutrition disorders
  • Kidney damage
  • Fits
  • Headaches
  • Depression
  • Imagined sensations (hallucinations)
  • Nervousness
  • Increase or decrease in urine production
  • Unsteadiness
  • Dizziness
  • Sleeplessness
  • Weakness
  • Tiredness,
  • Increased sensitivity to light
  • Stomach pains
  • Fixed drug eruption
  • Erythema multiforme
  • Anaphylactic reaction
  • Allergic myocarditis
  • Erythema multiforme
  • Toxicoderma
  • Exfoliative dermatitis
  • Angioedema
  • Pyrexia
  • Chills
  • Hypersensitivity
  • Vasculitis resembling Henoch-Schönlein purpura
  • Serum sickness
  • Serum sickness-like syndrome
  • Generalized allergic reactions
  • Generalized skin eruptions
  • Fixed drug eruption
  • Photosensitivity
  • Conjunctival
  • Scleral injection
  • Pruritus
  • Urticaria
  • Rash
  • Periarteritis nodosa
  • Systemic lupus erythematosus
Stop taking SEPTRIN and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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.

SEPTRIN Sugar-Free Suspension is a thick, pink cherry flavoured liquid in a 100 mL bottle.

What SEPTRIN contains

Active ingredient
(main ingredient)		Every 5 mL of Septrin Sugar-Free Paediatric Suspension contains 40 mg trimethoprim and 200 mg sulfamethoxazole.
Other ingredients
(inactive ingredients)
  • carmellose sodium
  • saccharin sodium
  • cellulose-dispersible
  • glycerol
  • polysorbate 80
  • citric acid – anhydrous
  • sorbitol
  • ethanol
  • water
  • sunset yellow FCF (CI 5985)
  • allura red AC (CI 16035)
  • Cherry Flavour Artif F1242 (PI 286)
  • methyl hydroxybenzoate
  • sodium benzoate
Potential allergenscontains Methyl hydroxybenzoate, Sodium benzoate and Saccharin sodium.

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

What SEPTRIN looks like

Septrin Sugar-Free Paediatric Suspension

AUST R 11000

Who distributes SEPTRIN

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was revised in September 2024

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Septrin Sugar Free Oral Liquid

Active ingredient

Trimethoprim; Sulfamethoxazole

Schedule

S4

 

1 Name of Medicine

Trimethoprim/sulfamethoxazole.

2 Qualitative and Quantitative Composition

Each 5 mL of Septrin Sugar Free Oral Liquid contains 40 mg trimethoprim and 200 mg sulfamethoxazole.

Excipient(s) with known effect.

Hydroxybenzoate, benzoate and saccharin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

A pink suspension with a characteristic cherry odour.

4 Clinical Particulars

4.1 Therapeutic Indications

Upper and lower respiratory tract infections, renal and urinary tract infections, genital tract infections, gastrointestinal tract infections, skin and wound infections, septicaemias, and other infections caused by sensitive organisms.

4.2 Dose and Method of Administration

In the majority of acute infections, Septrin should be given for at least 5 days or until the patient has been symptom free for 2 days.

Dosage.

Children under 12 years.

6 to 12 years.

5 to 10 mL Septrin Paediatric Suspension every twelve hours.

2 to 5 years.

2.5 to 5 mL Septrin Paediatric Suspension every twelve hours.

Under 2 years.

2.5 mL Septrin Paediatric Suspension every twelve hours.
These amounts approximate to a dose of 6 mg/kg trimethoprim daily plus 30 mg/kg sulfamethoxazole daily. For severe infections dosage may be increased by 50%.
Treatment of Pneumocystis carinii pneumonitis. The recommended dosage for patients with documented Pneumocystis carinii 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. The aim is to obtain peak plasma or serum levels of > 5 microgram/mL (see Section 4.8 Adverse Effects (Undesirable Effects)).
Use in the elderly. See Section 4.4 Special Warnings and Precautions for Use.
Dosage in patients with reduced renal function. The following dosage regimens have been published for the administration of Septrin to patients with reduced kidney function. See Table 1.

4.3 Contraindications

Septrin should not be given to patients with a history of sulphonamide or trimethoprim sensitivity or a hypersensitivity to any of the excipients listed in Section 6.1.
Marked liver parenchymal damage (severe impairment of liver) or severe renal insufficiency, where repeated measurements of the plasma concentration cannot be performed.
Except under careful supervision, Septrin should not be given to patients with serious haematological disorders. Septrin has been given to patients receiving cytotoxic therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Septrin should not be given to patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulphonamides and in patients with documented megaloblastic anemia due to folate deficiency, evidence of marked parenchymal damage, or blood dyscrasia.
Septrin should not be given to patients with acute porphyria.
Septrin should not be used in pregnancy and nursing mothers because products containing a sulphonamide may cause kernicterus.
Septrin should not be given to premature babies or to infants during the first 8 weeks of life.
Septrin should not be used in the treatment of streptococcal pharyngitis. Clinical studies have documented that patients with Group A Beta-haemolytic streptococcal tonsillopharyngitis have a greater incidence of bacteriologic failure when treated with Septrin than do those patients treated with penicillin, as evidenced by failure to eradicate this organism from the tonsillopharyngeal area.

4.4 Special Warnings and Precautions for Use

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, fulminant hepatic necrosis, agranulocytosis, immune thrombocytopenia aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.
Sulfonamides, including sulfonamide containing products such as trimethoprim/sulfamethoxazole, should be discontinued at the first appearance of skin rash or any sign of adverse reaction. In rare instances, a skin rash may be followed by a more severe reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis and serious blood disorder.
Clinical signs such as rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura or jaundice may be early indications of serious reactions.
Cough, shortness of breath and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.
Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) 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 and of DRESS is within the first two to eight weeks after drug administration.
If symptoms or signs of SJS, TEN (e.g. progressive skin rash often with blisters, sores, peeling of skin, body aches or mucosal lesions) or DRESS (e.g. fever, eosinophilia) are present, Septrin treatment should be discontinued (see Section 4.8).
The best results in managing SJS, TEN and 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 and DRESS with the use of Septrin, Septrin 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 acute generalised exanthematous pustulosis (AGEP) (see Section 4.8); it requires cessation of treatment and contraindicates any new administration of Septrin alone or in combination with other drugs.
Regular blood counts are advisable for patients receiving long term therapy to monitor any asymptomatic changes in haematological properties that could develop from folate deficiency. Most haematological disorders resulting from folate deficiency respond to administration of calcium folinate or removal of Septrin treatment.
Septrin can cause a liver disease called fulminant hepatic necrosis that may be life-threatening. Symptoms include yellowing of the skin and whites of the eyes (jaundice), pain in your upper right abdomen, swelling of the abdomen, nausea (feeling sick) and vomiting (being sick). If patients experience any of these symptoms, the treatment with Septrin should be immediately stopped.
Septrin can cause a blood condition called agranulocytosis, where the number of white cells in the blood becomes dangerously low. Symptoms of this can include sudden fever, chills, a sore throat, feeling weak. Patients can also experience fast heart rate or fast breathing. If patients experience any of these symptoms, the treatment with Septrin should be immediately stopped.
Septrin can cause aplastic anemia, where the bone marrow is unable to make enough blood cells from being damaged. Symptoms of this can include feeling tired, feeling short of breath, pale skin, unexplained or easy bruising, fever, chills, sore throat, and a general feeling of being unwell. If patients experience any of these symptoms, the treatment with Septrin should be immediately stopped.
Septrin can cause an allergic reaction in the lungs and in the airways, where the airways can close up and make breathing difficult, and can be life-threatening if the person does not get medical help. Symptoms include difficulty breathing, coughing, wheezing, and a feeling of tightness in the chest. If patients experience any of these symptoms, the treatment with Septrin should be immediately stopped.

Use in the elderly.

The use of Septrin 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, 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) 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 or without purpura has been reported. Appropriate dosage adjustments should be made for patients with impaired kidney function (see Section 4.2 Dose and Method of Administration).
Close supervision is recommended when Septrin is used in elderly patients or in patients taking high doses of Septrin as these patients may be more susceptible to hyperkalemia and hyponatremia.
The appearance of skin rashes, particularly in elderly patients, warrants the immediate removal of treatment.
Special care should be exercised when treating the elderly or suspected folate-deficient patients; folate supplementation should be considered.
In view of the increased risk of severe adverse reactions in the elderly, consideration should be given to whether Septrin is the antibacterial of choice in this age group.

Use in treatment of and prophylaxis for Pneumocystis carinii pneumonitis in patients with acquired immunodeficiency syndrome (AIDS).

Because of their unique immune dysfunction, AIDS patients may not tolerate or respond to Septrin in the same manner as non-AIDS patients. The incidence of side effects, particularly rash, severe hypersensitivity reactions, fever, leukopenia, neutropenia, thrombocytopenia and elevated aminotransferase (transaminase) values with Septrin therapy in AIDS patients who are being treated for Pneumocystis carinii pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of Septrin in non-AIDS patients.
The incidence of hyperkalemia and hyponatremia appears to be increased in AIDS patients receiving sulfamethoxazole and trimethoprim. If a patient develops skin rash or any sign of adverse reaction, therapy with Septrin should be re-evaluated.
Rhabdomyolysis has been reported in HIV positive patients receiving trimethoprim-sulfamethoxazole for prophylaxis or treatment of Pneumocystis carinii pneumonitis. In some cases, rhabdomyolysis led to acute renal failure requiring emergency dialysis.
Severe hypersensitivity reactions have also been reported in HIV-infected patients on re-exposure to sulfamethoxazole and trimethoprim, sometimes after a dosage interval of a few days.
Concomitant use of leucovorin for the acute treatment of Pneumocystis carinii pneumonitis in patients with HIV infection was associated with increased rates of treatment failure and morbidity.

Use in glucose-6-phosphate dehydrogenase deficiency.

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

Use in patients known or suspected to be at risk of acute porphyria.

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.

Pseudomembranous colitis or Clostridium difficile - associated disease (CDAD).

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including trimethoprim/sulfamethoxazole. A toxin produced with Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild diarrhoea to life threatening fatal colitis. It is important to consider this diagnosis in patients who develop diarrhoea or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). CDAD has been reported to occur over 2 months after the administration of antibacterial agents. Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against Clostridium difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Surgical intervention may be required in certain severe cases.
Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.
Drugs which delay peristalsis (e.g. opiates and diphenoxylate with atropine (Lomotil)) may prolong and/or worsen the condition and should not be used.
Fluids, electrolytes, and protein replacement therapy should be provided when indicated.
Even if an organism is sensitive to trimethoprim, if it is not sensitive to sulfamethoxazole the combination should not be used, to avoid unnecessary exposure to the potential side effects of the sulphonamide components.

Patients with thrombocytopenia.

Sulfamethoxazole/trimethoprim-induced thrombocytopenia may be an immune-mediated disorder and can be life threatening. Symptoms of this include being easily bruised, a rash on the skin that appears tiny pinpoint-sized reddish or purple spots, usually on the lower legs, bleeding from the gums or nose, and blood in the urine or stool. If patients experience any of these symptoms, the treatment with Septrin should be immediately stopped. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole/trimethoprim.

Patients with gastrointestinal tract infection.

Clinicians should be aware that first line therapy in the management of all patients with diarrheal disease is the maintenance of adequate hydration.

Patients with renal or hepatic impairment.

For patients with known renal or hepatic impairment special measures should be adopted including a reduced or less frequent dosage is recommended in order to avoid accumulation of trimethoprim in the blood (see Section 4.2 Dose and Method of Administration). 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. Septrin should not be used when the serum creatinine level is above 2 mg per 100 mL, in order to avoid possible permanent impairment of renal function.

Urinary output.

An adequate urinary output should be maintained at all times, especially when malnutrition is suspected. Evidence of crystalluria in vivo is rare, although sulphonamide crystals have been noted in cooled urine from treated patients. In patients suffering from malnutrition or hypoalbuminaemia this risk may be increased.
As with other sulphonamide preparations, critical appraisal of benefit versus risk should be made in patients with liver damage, renal damage, urinary obstruction, allergies or bronchial asthma. Severe hepatic parenchymal damage may result in changes in the absorption and metabolism of sulfamethoxazole and trimethoprim. In patients with renal impairment, a reduced or less frequent dosage is recommended in order to avoid accumulation of trimethoprim in the blood (see Section 4.2 Dose and Method Administration).
Nonionic 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. See the special dosage table for use in renal impairment.

Patients with severe atopy, severe allergy or bronchial asthma.

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

Folate.

Regular blood counts are advisable for patients on long-term therapy, in patients predisposed to folate deficiency (i.e. the elderly, chronic alcoholics and rheumatoid arthritis), in malabsorption syndromes, malnutrition states, during the treatment of epilepsy with anticonvulsant drugs (i.e. phenytoin, primidone, or barbiturates), severe allergy or bronchial asthma. There is a possibility of asymptomatic changes in haematological laboratory indices due to a lack of available folate. Changes indicative of folate deficiency may be reversed by administration of folinic acid however this needs to be done with caution due to possible interference with antimicrobial efficacy.
Special care should be exercised in treating elderly or suspected folate deficient patients; folate supplementation should be considered.
A folate supplement should also be considered with prolonged high dosage of Septrin. Urine analysis and renal function tests should be performed during long term therapy particularly in patients with reduced renal function.
The possibility of superinfection with a nonsensitive organism should be borne in mind.
Trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

Haemophagocytic lymphohistiocytosis (HLH).

Cases of HLH have been reported very rarely in patients treated with Septrin. 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) and is associated with high mortality rates if not recognized early and treated. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately. If diagnosis of HLH is established, cotrimoxazole treatment should be discontinued.

Respiratory toxicity.

Very rare, severe cases of respiratory toxicity, sometimes progressing to Acute Respiratory Distress Syndrome (ARDS), have been reported during Septrin treatment. The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function may be preliminary signs of ARDS. In such circumstances, Septrin should be discontinued and appropriate treatment given.

Treatment of streptococcal pharyngitis due to group A beta-haemolytic streptococci.

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.

Phenylalanine metabolism.

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

Patients with hyperkalaemia and hyponatraemia.

Close monitoring of serum potassium and sodium is warranted in patients at risk of hyperkalaemia and hyponatraemia. Renal function should be closely monitored and dosage should be adjusted for renal function (see Section 4.2 Dose and Method of Administration).
The risk factors for hyperkalemia are high trimethoprim dosage, renal insufficiency, hypoaldosteronism, older age, dietary potassium and other drugs that impair potassium excretion.
Hyperkalemia is generally reversible on discontinuation of trimethoprim. In patients presented with hyperkalemia due to Septrin, Septrin can be discontinued and appropriate standard potassium-lowering therapy instituted.

Metabolic acidosis.

Septrin has been associated with metabolic acidosis when other possible underlying causes have been excluded. Close monitoring is always advisable when metabolic acidosis is suspected.

Patients with serious haematological disorders.

Except under careful supervision Septrin should not be given to patients with serious haematological disorders (see Section 4.8). 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 antibiotics in Septrin 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.
Functional inhibition of the renal tubular secretion of creatinine may produce a spurious fall in the estimated rate of creatinine clearance.
Septrin may affect the results of thyroid function tests.
The possibility of superinfection with a non-sensitive organism should be borne in mind.

Fluid overload.

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

Paediatric use.

Safety has not been established in infants less than 2 months old and is not recommended for use. Trimethoprim and sulfamethoxazole should be used with caution in children who have the fragile X chromosome, as folate depletion may worsen the psychomotor regression associated with the disorder (see Section 4.3 Contraindications).

Effects on laboratory tests.

Septrin, specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA).
The presence of trimethoprim and sulfamethoxazole may also interfere with the Jaffe alkaline picrate reaction assay for creatinine resulting in over estimations of about 10% in the range of normal values. The creatinine clearance is reduced: the renal tubular secretion of creatinine is decreased whilst the glomerular filtration remains unchanged.
The Lactobacillus casei serum folate assay and the L. leishmanii serum vitamin B12 assay are affected by Septrin.

Development of drug resistant bacteria.

Prescribing Septrin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Diuretics (thiazides).

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

Pyrimethamine.

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

Warfarin.

Septrin 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.

Phenytoin.

Septrin prolongs the half-life of phenytoin and, if coadministered, the prescriber should be alert for excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels is advisable.
Interaction with sulphonylurea hypoglycaemic agents is uncommon, but potentiation has been reported.

Rifampicin.

Concurrent use of rifampicin and Septrin results in a shortening of the plasma half-life of trimethoprim after a period of about one week. This is thought to be of clinical significance.
Trimethoprim is an inhibitor of cytochrome P450 2C8 enzyme and may interact with other drugs that are primarily metabolized by the 2C8 isoform. Sulfamethoxazole is an inhibitor of cytochrome P450 2C9 and may interact with other drugs that are primarily metabolized by the 2C9 isoform.
Interaction with sulphonylurea hypoglycemic agents has been reported.

Cyclosporin.

Reversible deterioration in renal function has been observed in patients treated with Septrin and cyclosporin following renal transplantation.

Methotrexate.

Sulphonamides can displace methotrexate from plasma protein binding sites, thus increasing free methotrexate concentrations. If Septrin is considered appropriate therapy in patients receiving other antifolate drugs, such as methotrexate, a folate supplement should be considered (see Section 4.4 Special Warnings and Precautions for Use).
Cases of pancytopenia have been reported in patients taking trimethoprim/sulfamethoxazole in combination with methotrexate. Most of these patients were on long-term methotrexate therapy and/or predisposed to folate deficiency, and none of them were reported to have received a prophylactic folinic acid supplement (see Section 4.4 Special Warnings and Precautions for Use).
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.
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.

Digoxin.

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

Zidovudine.

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

Lamivudine.

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

Hyperkalaemia.

Caution should be exercised in patients taking any other drugs that can cause hyperkalaemia, for example ACE inhibitors, angiotensin receptor blockers and potassium-sparing diuretics such as spironolactone. Concomitant use of trimethoprim-sulfamethoxazole (Septrin) may result in clinically relevant hyperkalaemia.

Repaglinide.

Trimethoprim may increase the exposure of repaglinide which may result in hypoglycaemia.

Folinic acid.

Folinic acid supplementation has been shown to interfere with the antimicrobial efficacy of trimethoprim-sulfamethoxazole. This has been observed in Pneumocystis jirovecii pneumonia prophylaxis and treatment.

Contraceptives.

Oral contraceptive failures have been reported with antibiotics. The mechanism of this effect has not been elucidated. Women on treatment with antibiotics should temporarily use a barrier method in addition to the oral contraceptive, or choose another method of contraception.

Azathioprine.

There are conflicting clinical reports of interactions between azathioprine and trimethoprim-sulfamethoxazole, resulting in serious haematological abnormalities.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of Septrin on human fertility has not been established. Reproduction studies in rats with oral dosage up to 70 mg/kg/day trimethoprim plus 350 mg/kg/day sulfamethoxazole have not revealed evidence of impaired fertility.
(Category C)
Septrin should not be used in pregnancy, particularly in the first trimester, unless clearly necessary.
Trimethoprim and sulfamethoxazole cross the placenta and their safety in human pregnancy has not been established.
Sulphonamides may cause kernicterus, jaundice and haemolytic anaemia in the newborn (by displacing bilirubin from plasma albumin) and should therefore be avoided as far as possible during the last month of pregnancy. This theoretical risk of kernicterus is particularly relevant in infants at increased risk of hyperbilirubinaemia, such as those who are preterm and those with glucose-6-phosphate dehydrogenase deficiency. Trimethoprim and sulfamethoxazole may interfere with folic acid metabolism and exposure during organ development may give rise to birth defects typical of folic acid antagonism.
Trimethoprim and sulfamethoxazole, alone and in combination, have produced teratogenic effects (cleft palate and other foetal abnormalities) in some studies in rats receiving dosages exceeding the usual human dosage. In some rabbit studies, an overall increase in foetal loss was associated with trimethoprim doses 6 times the usual human dose. Septrin should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. If a trimethoprim/sulphonamide combination is given during pregnancy, folic acid supplementation may be required.
 Both trimethoprim and sulfamethoxazole are excreted in breast milk at concentrations comparable or somewhat lower than that in the blood. Sulfonamides may cause kernicterus, jaundice and haemolytic anaemia and hypersensitivity exists in the newborn. It is recommended that the possible risks should be balanced against the expected therapeutic effect. Administration of Septrin 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 should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia (see Section 4.3 Contraindications).

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 following reactions have been reported from the use of oral Septrin.
Haematological changes have been observed in some patients, particularly the elderly, in those with hepatic or renal dysfunction, or in those with poor folate status. While rare, fatalities have been recorded in at-risk patients so they should be observed carefully. The great majority of these changes were mild, asymptomatic, and proved reversible on withdrawal of the drug; in some instances, this was necessary before therapy could be completed.
Skin and systemic reactions may occur. Fatalities have been reported rarely. Jaundice has also rarely occurred and has usually been mild and transient, frequently occurring in patients with a past history of infectious hepatitis.
On the whole, however, the nature of adverse reactions generally corresponds with what one would expect from a sulphonamide of moderately low toxicity, when the contraindications are strictly respected and recommended doses are used. Percentage incidence figures cannot be precise but have been estimated from the published literature at 6.8% of cases treated.
Sensitivity reactions and gastrointestinal symptoms comprised nearly three-quarters of the adverse reactions reported.
The sulphonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycaemic agents. Cross sensitivity may exist with these agents.
At the high dosages used for the therapy of Pneumocystis carinii pneumonitis in patients with acquired immune deficiency syndrome (AIDS), rash, fever, neutropenia, thrombocytopenia, raised liver enzymes, hyperkalaemia and hyponatraemia have been reported, necessitating cessation of therapy. If signs of bone marrow depression occur, the patient may be given calcium folinate supplementation. Severe hypersensitivity reactions have also been reported in HIV infected patients on re-exposure to cotrimoxazole, sometimes after a dosage interval of a few days.
General adverse effects include weakness, fatigue, insomnia, vision troubles, alopecia, epistaxis, edema. Monilial overgrowth is common.

Allergic adverse effects.

Toxicoderma, exfoliative dermatitis, serum sickness, generalized skin eruptions, pruritus, urticaria, anaphylactoid reactions (sweating and collapse).

Metabolism and nutrition disorders.

Close supervision is recommended when cotrimoxazole is used in elderly patients or in patients taking high doses of cotrimoxazole as these patients may be more susceptible to hyperkalaemia and hyponatraemia.

Cardiovascular adverse effects.

QT prolongation.

Gastrointestinal adverse effects.

Pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, dry mouth, nausea, vomiting, pyrosis, gastric intolerance, gastritis or gastroenteritis, dyspepsia, emesis, constipation, flatulence, tooth and/or tongue discoloration.

Genitourinary adverse effects.

Kidney changes (as indicated by abnormal elevations in blood urea nitrogen, blood non-protein nitrogen, serum creatinine and urine protein levels), hematuria, urgency, and dysuria.

Hepatic/biliary/pancreatic adverse effects.

Hypoprothrombinemia.
Hepatic changes including fatalities have been recorded in at-risk patients. Cholestatic jaundice and hepatic necrosis may be fatal.

Neurologic adverse effects.

Tremor.
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.

Tabulated list of adverse reaction.

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, not known - cannot be estimated from the available data. See Table 2.

Description of selected adverse reactions.

Aseptic meningitis.

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.

Pulmonary hypersensitivity reactions.

Cough, dyspnoea and lung infiltration may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal.

Hepatobiliary disorders.

Jaundice cholestatic and hepatic necrosis may be fatal.

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 (see Section 4.4).
As with any other drug, allergic reactions such as an itchy rash and hives may occur in patients with hypersensitivity to the components of the drug. Very rare cases of acute generalised exanthematous pustulosis (AGEP) have been observed (see Section 4.4). Anaphylactic reaction, allergic myocarditis, erythema multiforme, toxicoderma, exfoliative dermatitis, angioedema, pyrexia, chills, hypersensitivity, vasculitis resembling Henoch-Schonlein purpura, serum sickness, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, fixed drug eruption, photosensitivity, conjunctival and scleral injection, pruritus, urticaria, and rash. In addition, periarteritis nodosa and systemic lupus erythematosus and anaphylactoid reactions (sweating and collapse) have been reported.

Effects associated with Pneumocystis jirovecii pneumonitis (PJP) management.

Severe hypersensitivity reactions, rash, pyrexia, neutropenia, thrombocytopenia, hepatic enzyme increased, hyperkalaemia, hyponatraemia and rhabdomyolysis.
At the high dosages used for PJP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. Severe hypersensitivity reactions have been reported in PJP 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 PJP.

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 http://www.tga.gov.au/reporting-problems and to also contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Acute.

The amount of a single dose of Septrin that is either associated with symptoms of overdosage or is likely to be life threatening has not been reported. Signs and symptoms of overdosage reported with sulphonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, haematuria and crystalluria may be noted. 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.

Chronic.

Use of Septrin at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anaemia.

Treatment.

Acute.

General principles of treatment include use of activated charcoal (where physiochemically appropriate) and the administration of intravenous fluids if urine output is low and renal function is normal. 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 not effective and haemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole.

Chronic.

If signs of bone marrow depression occur, the patient should be given leucovorin; 5 to 15 mg daily has been recommended by some investigators.
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 competitively inhibits the utilisation of para-aminobenzoic acid in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim reversibly inhibits bacterial dihydrofolate reductase (DHFR), an enzyme active in the folate metabolic pathway converting dihydrofolate to tetrahydrofolate. 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.
Trimethoprim binds to plasmodial DHFR, but less tightly than to the bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.

Clinical trials.

The majority of common Gram negative and Gram positive pathogenic bacteria are sensitive in vitro to trimethoprim and sulfamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. These organisms include E. coli, Neisseria, Salmonella, Klebsiella, Enterobacter, Shigella, Vibrio cholerae and Bordetella pertussis, Streptococcus, Staphylococcus, Pneumococcus. Septrin is usually active against the problem organisms Haemophilus influenzae and Proteus. See Table 3.
Septrin is insensitive against Pseudomonas aeruginosa, Mycoplasma, Ureoplasma urealyticum, Mycobacterium tuberculosis, Bacteroides species, Lactobacillus species and Treponema pallidum.
In vitro studies have shown that bacterial resistance develops more slowly with Septrin (trimethoprim + sulfamethoxazole) than with either trimethoprim or sulfamethoxazole alone.
Septrin is also active against the protozoan Pneumocystis carinii (see Section 4.2 Dose and Method of Administration).
Satisfactory sensitivity testing is achieved only with recommended media free from inhibitory substances, especially thymidine and thymine.

Disc susceptibility testing.

Dilution or diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of "susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration, trimethoprim and sulfamethoxazole are rapidly and nearly completely absorbed. Peak levels in the blood occur between one and four hours after ingestion and the level attained is dose related. Steady-state levels in adults are reached after dosing for 2-3 days. Neither component has an appreciable effect on the concentrations achieved in the blood by the other.
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, saliva, sputum and vaginal secretions. Trimethoprim is found in the aqueous humour, breast milk, cerebrospinal fluid, middle ear fluid, synovial fluid and tissue (interstitial) fluid. Trimethoprim passes into amniotic fluid and foetal tissue, reaching concentrations approximating those of maternal serum.

Distribution.

Approximately 44-50% of trimethoprim in the plasma is protein bound.

Metabolism.

The half-life in man is in the range 8.3-31 hours (mean 14.5 hours) in the presence of normal renal function. It is increased by a factor of 1.5-3.0 when the creatinine clearance is less than 10 mL/minute. There appears to be no significant difference in the elderly compared with young patients.

Excretion.

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 20-50% of the plasma concentration.
Approximately 66-70% of sulfamethoxazole in the plasma is protein bound. The half-life in man is in the range 6.1-22 hours (mean 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

Genotoxicity.

Bacterial mutagenic studies have not been performed with Septrin. Trimethoprim did not exhibit mutagenic activity in the Ames test, and no chromosomal damage was observed in human leukocytes cultured in vitro with trimethoprim concentrations exceeding those attained in blood during therapy with the drug.

Carcinogenicity.

Long-term studies in animals to evaluate the carcinogenic potential of Septrin have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Septrin Sugar Free Oral Liquid: sorbitol, ethanol, Cherry Flavour Artif F1242 (PI 286), sunset yellow, allura red, citric acid, cellulose, glycerol, polysorbate 80, sodium carmellose, saccharin sodium, methyl hydroxybenzoate, sodium benzoate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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

Suspension.

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Septrin Paediatric Suspension sugar free (cherry flavour): trimethoprim 40 mg/5 mL and sulfamethoxazole 200 mg/5 mL, pink suspension with a characteristic cherry odour. Free from undispersed material. 100 mL bottle (glass).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Trimethoprim is a white to light yellow, odourless, bitter compound.
Sulfamethoxazole is an almost white, odourless, tasteless compound.

Chemical structure.


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

CAS number.

738-70-5.
Chemical name: N1-(5-methyl-3-isoxazolyl) sulphanilamide.
Molecular formula: C10H11N3O3S.
Molecular weight: 253.28 g/mol.

CAS number.

723-46-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes