Owing to the sometimes serious side effects of Bactrim and the emergence of resistance, a riskbenefit
assessment versus other active substances that may also be suitable for these indications
should always be carried out prior to use of Bactrim.
Infections caused by co-trimoxazole -susceptible organisms, such as:
Infections of the upper and lower respiratory tract and ear: acute exacerbations of chronic
bronchitis, bronchiectasis, pneumonia (including Pneumocystis jirovecii (formerly carinii)
pneumonia), sinusitis, otitis media.
Infections of the urogenital system: acute and chronic cystitis, pyelonephritis, urethritis, prostatitis.
Infections of the gastrointestinal tract: travellers' diarrhoea, chronic typhoid fever carriers, cholera
(as an adjunct to fluid and electrolyte intake).
Cotrimoxazole should be used for the following infections only if other currently recommended
antibiotics cannot be administered:
Typhoid fever, paratyphoid A and B, Salmonella enteritis with septic progression in
immunocompromised patients.

Note:
Gastroenteritis caused by Salmonella enteritidis should generally not be treated with Bactrim, as
the course of the disease is not affected and excretion is even prolonged (for exception, see above).
Other infections, if caused by susceptible organisms: acute brucellosis, nocardiosis, mycetoma
(unless caused by true fungi), South American blastomycosis (Paracoccidioides brasiliensis).
In osteomyelitis as a last-line medicinal product for (i.e. where there is a contraindication to
vancomycin, for example), for multi-resistant organisms and where susceptibility to Bactrim has
been demonstrated.
Official recommendations on the appropriate use of antibiotics should be followed, in particular
recommendations on use to prevent the increase in antibiotic resistance.
Bactrim should be used only to treat or prevent infections that are proven or strongly suspected to
be caused by susceptible bacteria or other susceptible micro-organisms. In the absence of relevant
data, local epidemiology and susceptibility  patterns may contribute to empirical selection of the
appropriate antibiotic therapy.

Posology
Standard dosage
Bactrim is administered at 12-hourly intervals. As a rule, adults and children aged 12 and over
receive the forte tablets, and children under 12 years of age, receive the oral suspension.
The usual dosage for adults and children aged 12 and over:
TABLE 1

	Forte tablets
	morning	evening
Standard dosage	1	1
Minimum dosage and dosage for long-term treatment (more than 14 days)	½	½
High dosage (for severe cases)	1 ½	1 ½

 

Duration of treatment
For acute infections, treatment with the oral form should last at least 5 days.

Special dosage instructions
Acute uncomplicated urinary tract infections
To treat acute uncomplicated urinary tract infections in women, a single administration of 2–3 forte
tablets is recommended. These are best taken after the evening meal or at bedtime.
Patients with Pneumocystis jirovecii pneumonia
The recommended dosage is up to 20 mg TM per kg and 100 mg SMZ per kg per 24 hours, given
orally in equal divided doses every six hours for 14 days.
Table 2 below gives a general guide to the upper dosage limit based on body weight for patients
with Pneumocystis jirovecii pneumonia:
TABLE 2

 

Bodyweight [kg]	Dose – every 6 hours Forte tablets
8 16 24 32 40 48 64 80	- - - 1 - 1½ 2 2½

Pneumocystis jirovecii pneumonia prophylaxis
The recommended dosage for prophylaxis of Pneumocystis jirovecii pneumonia in adolescents and
adults is 1 forte tablet 3 times/week.
TABLE 3

Body surface area	Dose every 12 hours
(m2)	Tablets
0.26	--
0.53	1/2
1.06	1

 

Patients with nocardiosis
The recommended dosage for adults with nocardiosis is 3 - 4 forte tablets daily for at least
3 months. This dosage recommendation is to be adjusted to the patient's age, weight, renal function
and disease severity. Long-term treatment over the course of 18 months has been reported.

Patients with renal dysfunction
Dosage recommendation for patients with impaired renal function:

TABLE 4

Creatinine clearance	Recommended dosage regimen
> 30 ml/min	Standard dosage
15–30 ml/min	Half the standard dosage
< 15 ml/min	Should not be used (see "Contraindications")

 

Dialysis patients
Patients on haemodialysis should initially receive a standard starting dose of TM-SMZ, followed
by an additional half dose after each haemodialysis session.
Serum concentrations of the medicinal product should be monitored in order to adjust the dosage.
Patients on haemodialysis should be closely monitored for signs and symptoms of toxicity.
Peritoneal dialysis results in only minimal clearance of administered TM and SMZ. The use of
TM-SMZ in patients receiving peritoneal dialysis is not recommended.
Method of administration
Bactrim is best taken after meals with plenty of liquid.

- Hypersensitivity to the active substances, to sulphonamides or trimethoprim or any of the excipients listed under Composition. - Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (including a history thereof). - Congenital glucose-6-phosphate dehydrogenase deficiency in red blood cells, haemoglobin abnormalities such as Hb Köln and Hb Zurich. - Acute porphyria. - Neonates with hyperbilirubinaemia or glucose-6-phosphate dehydrogenase deficiency in red blood cells. - Marked damage to the liver parenchyma (e.g. acute hepatitis). - Severe renal insufficiency (creatinine clearance < 15 ml/min). - Pathological blood count changes such as megaloblastic anaemia due to folic acid deficiency, thrombocytopenia, granulocytopenia. - Use in premature babies or neonates during the first six weeks of life, as this can lead to an increased risk of kernicterus. - Use during the final trimester of pregnancy (see section 4.6 "Fertility, pregnancy and lactation"). - Combination with dofetilide (see section 4.5 "Interactions with other medicinal products and other forms of interaction")

Treatment is to be discontinued without delay at the first signs of rash or other severe side effects
(such as haematological side effects, for example).
Flu-like symptoms, sore throat or fever may be symptoms of blood count changes. If these
symptoms occur, blood counts must be carried out immediately.
Bactrim should be administered with caution to patients with a history of allergy or bronchial
asthma.
Very rare, severe cases of respiratory toxicity, sometimes progressing to Acute Respiratory Distress
Syndrome (ARDS), have been reported during Bactrim 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,
Bactrim should be discontinued and appropriate treatment given.
In connection with adverse effects such as blood dyscrasias (aplasia, agranulocytosis,
thrombopenia), severe cutaneous adverse reactions (SCARs), for example, severe erythema
multiforme (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), drug rash
with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis
(AGEP) as well as fulminant hepatic necrosis. Cases with a fatal outcome have been reported -
albeit rarely. Patients should be informed of the signs and symptoms of these serious side effects
and be closely monitored for the occurrence of skin reactions.

The risk of developing SJS, TEN or DRESS is highest in the first weeks of treatment. If signs or
symptoms of SJS, TEN or DRESS occur (e.g. a progressive skin rash, often with blistering or
accompanying mucosal lesions), treatment with Bactrim must be discontinued.
The course of SJS, TEN and DRESS is largely determined by early diagnosis and immediate
discontinuation of all suspect medicinal products, i.e. early discontinuation improves the prognosis.
After the occurrence of SJS, TEN or DRESS associated with the use of Bactrim, the patient must
never again be treated with Bactrim.
Cases of haemophagocytic lymphohistiocytosis (HLH) have been reported very rarely in patients
treated with Bactrim. HLH is a life-threatening syndrome of pathologic immune activation
characterised by clinical signs and symptoms of 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 a diagnosis of HLH is established, Bactrim
treatment should be discontinued.
Haematological events are more common in:
- the elderly, and
- people with existing folic acid deficiency (advanced age, pregnancy (see section 4.3
"Contraindications"), alcoholism, chronic hepatic insufficiency, malnutrition, chronic
malabsorption). These haematological changes are reversible after treatment with folic acid.
It is recommended that treatment with the trimethoprim-sulfamethoxazole combination not exceed
ten days in these patients.
Periodic haematological monitoring is necessary in the following cases:
- prolonged or repeated treatments,
- people over 65 years of age, and
- people with folic acid deficiency.
Use of the trimethoprim-sulfamethoxazole combination is not recommended in macrocytic
anaemia (see section 4.3 "Contraindications").

 

Patients to whom Bactrim must be administered for a prolonged period of time should have their
blood count checked regularly. Bactrim must be discontinued in the event of a significant reduction
in a cellular element compared with the norm.
Bactrim is not recommended during pregnancy or in women who are planning to have a baby
unless the benefit to the patient clearly outweighs the risk, as TM and SMZ cross the placental
barrier, affect foetal folic acid metabolism and may therefore pose a potential risk to the foetus,
and clinical studies have shown an increased risk of spontaneous abortion.
Women of childbearing potential who are planning to have a baby should take a pregnancy test
before starting treatment with Bactrim, and pregnancy should be ruled out.
Renal effects
Sulphonamides, including Bactrim, may cause increased diuresis, especially in patients with
cardiac oedema.
Close monitoring of serum potassium and renal function is required in patients who are receiving
high doses of Bactrim, as used in patients with Pneumocystis jirovecii pneumonia, or in patients
who are receiving standard doses of Bactrim and have underlying disorders of potassium
metabolism or renal insufficiency, or who are receiving medicinal products that cause
hyperkalaemia (see section 4.5 "Interactions with other medicinal products and other forms of
interaction").
During treatment with Bactrim, the patient should ensure adequate fluid intake in order to prevent
crystalluria.
Specific patient groups
In the elderly, in patients with additional complications, such as impaired renal and/or hepatic
function, as well as when other medicinal products are administered concomitantly, there is an
increased risk of serious side effects, depending on the dose and treatment duration.
In the event of impaired renal function, the dosage should be adjusted in accordance with the
specific dosing instructions. Patients with severe renal impairment (i.e. with a creatinine clearance
of 15–30 ml/min) who are receiving TM-SMZ should be closely monitored for toxicity symptoms
and signs such as nausea, vomiting and hyperkalaemia.
Patients with severe blood dyscrasias are to be treated with Bactrim only in exceptional cases.

 

Occasionally, the preparation has been administered to leukaemia patients who were under the
influence of cytostatic drugs; they displayed no additional adverse effect on the bone marrow or
peripheral blood count.
Patients with G6PD deficiency and patients with certain haemoglobin disorders (Hb Zurich, Hb
Köln) may develop cyanosis due to sulfhaemoglobinaemia or methaemoglobinaemia. Glucose-6-
phosphate dehydrogenase deficiency can induce haemolysis in susceptible patients regardless of
the dose (see section 4.3 "Contraindications").
To minimise the risk of adverse effects, treatment with Bactrim should be as short as possible,
especially in elderly patients.
Severe and persistent diarrhoea during or after therapy may be an indication of pseudomembranous
colitis, which must be treated immediately. In such cases, Bactrim should be discontinued and an
appropriate diagnostic work-up and therapy should be initiated (e.g. oral vancomycin, 4 x 250 mg
daily). Antiperistaltic agents are contraindicated.
If administered for a prolonged period of time, urine and renal function should be monitored
(especially in patients with kidney injury).
Given that Bactrim, like other antibiotics, can reduce the effectiveness of oral contraceptives,
female patients should be advised to take additional contraceptive measures during treatment with
Bactrim.
Prolonged therapy with Bactrim may lead to the proliferation of non-susceptible bacteria and fungi.
In the event of a superinfection, suitable therapy should be initiated immediately.
Caution is advised in patients with porphyria or thyroid dysfunction.
In elderly patients and in patients with renal insufficiency, haematological changes suggestive of
folic acid deficiency may occur; however, these can be reversed by means of folic acid treatment.
Caution is advised in patients who have an additional risk factor for folic acid deficiency, e.g.
phenytoin therapy with other folic acid antagonists, malnutrition.
Simultaneous administration of Bactrim and phenytoin is not recommended (see section 4.5
"Interactions with other medicinal products and other forms of interaction").
Cases of pancytopenia have been reported in patients who have received the combination of
trimethoprim and methotrexate. Simultaneous administration of Bactrim and methotrexate is not

recommended (see section 4.5 "Interactions with other medicinal products and other forms of
interaction").
Patients who are "slow acetylators" may have an increased risk of idiosyncratic reactions to
sulphonamides.
Bactrim forte and Bactrim Tablets (export)
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially
"sodium-free".

Pharmacokinetic interactions
Trimethoprim is an inhibitor of organic cation transporter 2 (OCT2) and a weak inhibitor of
CYP2C8. Sulfamethoxazole is a weak inhibitor of CYP2C9.
Raised blood digoxin levels may occur with concomitant Bactrim therapy, especially in elderly
patients.
Bactrim, given at standard doses, prolonged the phenytoin half-life by 39% whereas it decreased
phenytoin clearance by 27%. Simultaneous administration of Bactrim and phenytoin is not
recommended. If concomitant administration is essential, patients receiving phenytoin should be
monitored for signs of phenytoin toxicity, and serum phenytoin concentrations should be monitored.
Patients receiving sulfonylurea derivatives (such as glibenclamide, gliclazide, glipizide,
chlorpropamide and tolbutamide) or repaglinide, rosiglitazone or pioglitazone should be monitored
regularly for hypoglycaemia.
Sulphonamides, including sulfamethoxazole, may displace methotrexate from plasma protein
binding sites and interfere with its renal transport, thereby increasing the concentration of free
methotrexate and enhancing its action and haematological side effects. Simultaneous
administration of Bactrim and methotrexate is not recommended.
Bactrim may affect the required dose of oral antidiabetic agents.
Bactrim, like other antibiotics, may reduce the effectiveness of oral contraceptives. Female patients
should therefore be advised to take additional contraceptive measures during treatment with
Bactrim

Observed interactions
An increased incidence of thrombocytopenia with purpura has been observed in elderly patients
concomitantly receiving certain diuretics (primarily thiazides). The platelet count should therefore
be monitored regularly during use of diuretics.
On co-administration with Bactrim, there may be an increase in systemic exposure to active
substances that are primarily metabolised via CYP2C9, such as coumarins (warfarin,
acenocoumarol, phenprocoumon), phenytoin and sulphonylurea derivatives (glibenclamide,
gliclazide, glipizide, chlorpropamide and tolbutamide).
Coagulation should be monitored in patients who are being treated with coumarins.
Reversible impairment of renal function has been observed in patients treated with Bactrim and
ciclosporin following kidney transplantation.
Cases of pancytopenia have been reported in patients who have received the combination of
trimethoprim and methotrexate (see "Warnings and precautions"). Trimethoprim has a low affinity
for human dihydrofolate reductase, but it may increase the side effects of methotrexate, especially
in the presence of risk factors such as advanced age, hypoalbuminaemia, impaired renal function
and reduced bone marrow reserve, as well as in patients receiving high-dose methotrexate. At-risk
patients should be treated with folic acid or calcium folinate in order to counteract the effects of
methotrexate on haematopoiesis (rescue).
Occasional reports suggest that patients taking pyrimethamine for malaria prophylaxis in doses
exceeding 25 mg pyrimethamine weekly may develop megaloblastic anaemia when Bactrim is coadministered.
Due to the potassium-sparing effect of Bactrim, caution is advised when it is co-administered with
other substances that increase serum potassium levels, such as angiotensin-converting enzyme
inhibitors, angiotensin receptor blockers, potassium-sparing diuretics and prednisolone.
Frequent serum potassium monitoring is advised, especially in patients with underlying potassium
disorders, renal insufficiency or those receiving high doses of Bactrim.
When used concomitantly with Bactrim, there may be an increase in systemic exposure to active
substances transported by OCT2, such as dofetilide, amantadine, memantine and lamivudine.
Bactrim must not be used in combination with dofetilide (see section 4.3 "Contraindications").
There is evidence that TM inhibits the excretion of dofetilide via the kidneys. Simultaneous administration of trimethoprim 160 mg in combination with sulfamethoxazole 800 mg twice daily
and dofetilide 500 μg twice daily for 4 days resulted in a 103% increase in the area under the
concentration-time curve (AUC) of dofetilide and a 93% increase in peak plasma concentration
(Cmax). Dofetilide can cause prolongation of the QT interval with serious ventricular arrhythmia,
including torsade de pointes; these are directly dependent on the plasma concentration of dofetilide.
Patients treated with amantadine or memantine may have an increased risk of neurological adverse
events such as delirium or myoclonus. Toxic delirium after simultaneous intake of Bactrim and
amantadine has been reported.
When used concomitantly with Bactrim, there may be an increase in systemic exposure to active
substances that are primarily metabolised via CYP2C8, such as paclitaxel, amiodarone, dapsone,
repaglinide, rosiglitazone and pioglitazone.
Paclitaxel and amiodarone have a narrow therapeutic margin; simultaneous use with TM-SMZ is
therefore not recommended.
Both dapsone and Bactrim can cause methaemoglobinuria. Patients receiving dapsone in
combination with Bactrim should be monitored for methaemoglobinuria. Where possible,
alternative therapies should be considered.
Pharmacodynamic interactions
The incidence rate and severity of myelotoxic and nephrotoxic adverse reactions may be increased
when TM-SMZ is administered concomitantly with other medicinal products known to have
myelosuppressive or nephrotoxic properties, such as nucleoside analogues, tacrolimus,
azathioprine or mercaptopurine. Patients receiving TM-SMZ together with such medicinal
products should be monitored for haematological and/or renal toxicity. Alternatives to Bactrim
should be considered in patients receiving azathioprine or mercaptopurine.
Simultaneous use with clozapine, an active substance with considerable potential to induce
agranulocytosis, should be avoided.

Pregnancy
Bactrim is not recommended during pregnancy or in women who are planning to have a baby
unless the benefit to the patient clearly outweighs the risk, as TM and SMZ cross the placental barrier, affect foetal folic acid metabolism and may therefore pose a potential risk to the foetus,
and clinical studies have shown an increased risk of spontaneous abortion.
Women of childbearing potential who are planning to have a baby should take a pregnancy test
before starting treatment with Bactrim, and pregnancy should be ruled out.
A congenital G6PD deficiency may result in neonatal haemolysis.
First trimester
Two large-scale observational studies showed that women treated with TM alone and in
combination with SMZ in the first trimester had a 2- to 3.5-fold increased risk of spontaneous
abortion compared with no exposure to antibiotics or exposure to penicillins.
The risk of congenital malformations in women undergoing Bactrim therapy during early pregnancy
could not be conclusively demonstrated. At very high doses of Bactrim, animal studies produced
malformations typical of folic acid antagonism.
Studies in animals have shown that very high doses of Bactrim cause foetal malformations typical
of folic acid antagonism (see "Preclinical data"). However, two studies suggest that, when folic acid
antagonists including TM-SMZ are given to a woman during the three months after her last
menstrual period, there is a possibility of specific neural tube and cardiac defects. The cause is
suspected to be interference with folates. These results have yet to be confirmed and are not, in
themselves, sufficient to advise a termination. If the trimethoprim-sulfamethoxazole combination
is nevertheless used at the beginning of pregnancy, dietary supplementation with folic acid for the
duration of treatment can be suggested but its effectiveness in preventing these abnormalities has
not yet been demonstrated. It is recommended that women who are pregnant or planning to have a
baby and cannot be given an alternative to Bactrim treatment receive an additional 5 mg of folic
acid per day during necessary Bactrim treatment.
Third trimester
Bactrim is contraindicated in the last trimester as it could lead to an increased risk of neonatal
kernicterus (see section 4.3 “Contraindications” and section 5.2.2 Distribution").
Lactation
TM and SMZ are excreted in human milk. Although the amount ingested by the infant is extremely
small, the benefit to the mother should still be weighed carefully against the risk to the infant (kernicterus, hypersensitivity) (see section 4.3 “Contraindications” and section 5.2.2
Distribution").

Bactrim has no influence on the ability to drive and use machines. However, adverse reactions that
interfere with these abilities, sometimes severely, are possible (see "Undesirable effects").

The main adverse effects include skin reactions and mild gastrointestinal symptoms, which have
occurred in about 5% of treatment periods.
The following adverse effects have been reported (by frequency and by MedDRA system organ
class):
"Very common" (≥ 1/10), "common" (≥ 1/100, < 1/10), "uncommon" (≥ 1/1000, < 1/100), "rare"
(≥ 1/10,000, < 1/1000), "very rare" (< 1/10,000), "not known" (cannot be estimated from the
available data).
Infections and infestations
Uncommon: fungal infections such as candidiasis.
Blood and lymphatic system disorders
Rare: leukopenia, granulocytopenia, thrombocytopenia, anaemia (megaloblastic,
immunohaemolytic, aplastic anaemia).
Very rare: agranulocytosis, methaemoglobinaemia, pancytopenia.
Most of the haematological changes observed have been mild, asymptomatic and reversible upon
discontinuation of the medicinal product.
Congenital disorders and pregnancy, puerperium and perinatal conditions
Not known: spontaneous abortion
Immune system disorders
Very rare: allergic reactions such as fever, angioedema, anaphylactoid reactions and serum
sickness.

Metabolism and nutrition disorders
Rare: hypoglycaemia in non-diabetic patients, generally occurring in the first few days of
treatment. Patients with impaired renal function, liver disease or malnutrition and patients receiving
high-dose TM-SMZ are particularly at risk.
Psychiatric disorders
Rare: hallucinations, delirium and psychosis, especially in elderly patients.
Nervous system disorders
Uncommon: convulsions.
Rare: neuropathy (including peripheral neuritis and paraesthesia).
Very rare: aseptic meningitis or meningitis-like symptoms, ataxia.
Not known: cerebral vasculitis.
Eye disorders
Very rare: uveitis.
Not known: retinal vasculitis.
Ear and labyrinth disorders
Very rare: dizziness, tinnitus.
Cardiac disorders
Very rare: allergic myocarditis, QT interval prolongation, torsade de pointes.
Vascular disorders
Very rare: purpura, Henoch-Schönlein purpura.
Not known: vasculitis, necrotising vasculitis, granulomatosis with polyangiitis, polyarteritis
nodosa.
Respiratory, thoracic and mediastinal disorders
Very rare: allergic pulmonary reactions (lung infiltration, interstitial and eosinophilic pneumonia,
respiratory insufficiency). These reactions are more common in AIDS patients.
Lung infiltration, which has been reported in connection with eosinophilic or allergic alveolitis,
may manifest as symptoms such as cough or dyspnoea.
Not known: pulmonary vasculitis.

Gastrointestinal disorders
Common: nausea, vomiting.
Uncommon: diarrhoea, pseudomembranous enterocolitis.
Rare: stomatitis, glossitis.
Not known: acute pancreatitis.
Hepatobiliary disorders
Common: increased transaminase levels.
Uncommon: increased bilirubin, hepatitis.
Rare: cholestasis.
Very rare: liver necrosis.
Not known: vanishing bile duct syndrome.
Skin and subcutaneous tissue disorders
Common: fixed drug eruption, exfoliative dermatitis, maculopapular rash, morbilliform rash,
erythema, pruritus, rashes.
These side effects are generally mild and rapidly reversible upon discontinuation of the preparation.
Uncommon: urticaria.
Not known: dermatosis, acute febrile neutrophilic dermatosis (Sweet's syndrome)
In common with many other medicinal products containing sulphonamides:
Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's
syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS), photosensitivity,
acute generalised exanthematous pustulosis.
Musculoskeletal and connective tissue disorders
Very rare: rhabdomyolysis.
Not known: arthralgia, myalgia.
Renal and urinary disorders
Common: elevated levels of blood urea nitrogen (BUN), elevated serum creatinine levels.

Uncommon: kidney dysfunction (to the point of kidney failure).
Rare: crystalluria.
Very rare: interstitial nephritis, increased diuresis, especially in patients with cardiac oedema.
Investigations
Very common: hyperkalaemia, hyponatraemia.
High-dose TM, as used in patients with Pneumocystis jirovecii pneumonia, induces a progressive
but reversible increase in the serum potassium concentration in a significant proportion of patients.
TM can cause hyperkalaemia very commonly (in 60% or more of patients), even at the
recommended doses, in patients who have potassium metabolism disorders or renal insufficiency
or who are being administered medication that causes hyperkalaemia.
Undesirable effects in HIV patients
HIV patients with frequent comorbidities and their treatments usually receive prolonged
prophylaxis or therapy of Pneumocystis jirovecii pneumonia with high doses of Bactrim. In these
patients, the spectrum of side effects – with the exception of a few additional side effects – is
approximately the same as in the general population without HIV infection. However, certain side
effects are more common (about 65%) and often more severe, with the result that treatment with
Bactrim has to be interrupted or discontinued in 20–25% of patients.
The following side effects, in particular, have been observed increasingly or additionally:
Blood and lymphatic system disorders
Very common: primarily neutropenia, but also anaemia, leukopenia, granulocytopenia and
thrombocytopenia.
Metabolism and nutrition disorders
Uncommon: hypoglycaemia.
Psychiatric disorders
Very rare: acute psychosis.

Nervous system disorders
Very rare: parkinsonian resting tremor, sometimes in combination with apathy, foot clonus and
splayed gait.
Gastrointestinal disorders
Very common: loss of appetite, nausea, vomiting, diarrhoea.
Very rare: pancreatitis.
Hepatobiliary disorders
Very common: increased transaminases, cholestatic jaundice.
Very rare: sometimes severe hepatitis.
Skin and subcutaneous tissue disorders
Very common: maculopapular rash that causes itching over time and is rapidly reversible upon
discontinuation of the preparation, usually with pruritus.
Rare: photosensitivity.
Musculoskeletal and connective tissue disorders
Very rare: arthralgia, myalgia.
Renal and urinary disorders
Uncommon: azotaemia, crystalluria.
General disorders and administration site conditions
Very common: fever, usually associated with skin rashes.
Investigations
Very common: hyperkalaemia.
High-dose TM, as used in patients with Pneumocystis jirovecii pneumonia, induces a progressive
but reversible increase in the serum potassium concentration in a significant proportion of patients.
TM can cause hyperkalaemia very commonly (in 60% or more of patients), even at the recommended doses, in patients who have potassium metabolism disorders or renal insufficiency
or who are being administered medication that causes hyperkalaemia.
Uncommon: hyponatraemia.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is very
important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions online via the Elvis
portal (Electronic Vigilance System). You can obtain information about this at
www.swissmedic.ch.

 

To report any side effect(s):
For Saudi Arabia:
• The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2340.
• Reporting hotline: 19999.
• E-mail: npc.drug@sfda.gov.sa
• Website: https://ade.sfda.gov.sa

 

 

Signs and symptoms
The following symptoms are possible in the event of an acute overdose: nausea, vomiting,
headache, dizziness, drowsiness, mental and visual disturbances; in severe cases, crystalluria,
haematuria and anuria.
Chronic overdose: bone marrow depression presenting as thrombocytopenia, leukopenia or other
blood dyscrasias as a result of folic acid deficiency.

Treatment
Depending on the symptom, the following measures should be considered: prevention of further
absorption, acceleration of renal excretion by forced diuresis (alkalinisation of the urine accelerates
SMZ excretion), haemodialysis (note: peritoneal dialysis is not effective), blood count and
electrolyte monitoring. These complications should be treated specifically in cases of marked blood
dyscrasias or jaundice. Calcium folinate, 3–6 mg IM for 5–7 days, maybe administered as an
antidote to the effect of TM on haematopoiesis.

ATC code: J01EE01
Mechanism of action
The two active substances in Bactrim elicit synergistic activity based on the blockade of two
enzymes that catalyse successive reactions in the biosynthesis of folinic acid in microoganisms.
Due to this mechanism of action, the bactericidal effect of Bactrim in vitro usually occurs at
concentrations at which the individual active substances have only a bacteriostatic effect. Bactrim
is also often effective against organisms that are resistant to one of the two components. Thanks to
the dual effect of Bactrim, the risk of widespread resistance developing is minimised.
The in vitro antibacterial effect of Bactrim extends to gram-positive and gram-negative pathogens
and includes the following organisms, although susceptibility may vary geographically:
Commonly susceptible organisms (MIC ˂80 mg/l)*
Cocci: Branhamella catarrhalis.
Gram-negative rods: Haemophilus parainfluenzae, Klebsiella oxytoca, other Klebsiella spp.,
Enterobacter aerogenes, Hafnia alvei, Serratia marcescens, Serratia liquefaciens, other Serratia
spp., Yersinia enterocolitica, other Yersinia spp., Vibrio cholerae.
Various gram-negative rods: Edwardsiella tarda, Alcaligenes faecalis, Burkholderia
(Pseudomonas) pseudomallei.

 

Based on available clinical experience, the following organisms should also be considered
susceptible: Brucella, Listeria monocytogenes, Nocardia asteroides, Pneumocystis jirovecii,
Cyclospora cayetanensis.
Partly susceptible organisms (MIC = 80–160 mg/l)*
Cocci: Staphylococcus aureus (methicillin-susceptible and methicillin-resistant), Staphylococcus
spp. (Coagulase-negative), Streptococcus pneumoniae (penicillin-susceptible, penicillinresistant).
Gram-negative rods: Haemophilus influenzae (β-lactamase-positive, β-lactamase-negative),
Haemophilus ducreyi, E. coli, Klebsiella pneumonia, Proteus mirabilis, Proteus vulgaris,
Morganella morganii, Shigella spp., Enterobacter cloacae, Providencia rettgeri, other
Providencia spp., Salmonella typhi, Salmonella enteritidis, Stenotrophomonas maltophilia
(formerly Xanthomonas maltophilia), Citrobacter freundii, other Citrobacter spp.
Various gram-negative rods: Acinetobacter lwoffi, Acinetobacter anitratus (primarily
A. baumanii), Aeromonas hydrophila.
Resistant organisms (MIC >160 mg/l) *
Burkholderia (Pseudomonas) cepacia, Pseudomonas aeruginosa, Mycoplasma spp.,
Mycobacterium tuberculosis, Treponema pallidum, Neisseria gonorrhoeae, Bacteroides, other
strictly anaerobic bacteria.
*SMZ equivalent
The local prevalence of bacterial resistance to Bactrim associated with the treated infection should
be known empirically when administering Bactrim.
In the case of infections caused by moderately susceptible organisms, it is recommended that a
sensitivity test be carried out to rule out any potential resistance. Susceptibility to Bactrim can be
determined by disk or dilution tests using standardised methods, as recommended by the European
Committee on Antimicrobial Susceptibility Testing (EUCAST). EUCAST recommends the
following susceptibility criteria:

Table 6

 

		Disk testa, Inhibition zone diameter (mm)	Dilution testb, MIC (g/mL)
			TM	SMZ
Enterobacteriaceae	Susceptible	 14	 2	 38
	Resistant	< 11	> 4	> 76
Acinetobacter spp.	Susceptible	 14	 2	 38
	Resistant	< 11	> 4	> 76
Stenotrophomonas maltophiliac	Susceptible	 16	 4	 76
	Resistant	< 16	> 4	> 76
Staphylococcus spp.	Susceptible	 17	 2	 38
	Resistant	< 14	> 4	> 76
Enterococcus spp.d	Susceptible	 50	 0.03	 0.57
	Resistant	< 21	> 1	> 19
Streptococcus pneumoniae	Susceptible	 18	 1	 19
	Resistant	< 15	> 2	> 38
Streptococcus groups A, B, C and G	Susceptible	≥ 18	≤ 1	≤ 19
	Resistant	< 15	> 2	> 38
Haemophilus influenzae & Haemophilus parainfluenzae	Susceptible	 23	 0.5	 9.5
	Resistant	< 20	> 1	> 19
Listeria monocytogenes	Susceptible	≥ 29	≤ 0.06	≤ 1.14
	Resistant	< 29	> 0.06	> 1.14
Pasteurella multocida	Susceptible	≥ 23	≤ 0.25	≤ 4.75
	Resistant	< 23	> 0.25	> 4.75
Moraxella catarrhalis	Susceptible	≥ 18	≤ 0.5	≤ 9.5
	Resistant	< 15	> 1	> 19

 

a Disk: 1.25 μg TM and 23.75 μg SMZ
b TM and SMZ at a 1:1 ratio plus 19
c Breakpoints are based on high-dose therapy, ≥ 240 mg trimethoprim and 1.2 g sulfamethoxazole, administered
together twice daily
d Activity of TM and TM-SMZ against enterococci is unclear; therefore the wild-type population is classified as
intermediate.
There are no EUCAST breakpoints available for the following species with CLSI breakpoints (disk [mm]; and
dilution [μg/mL]) given in brackets:
Burkholderia cepacia (S, ≥16; I, 11–15; R, ≤10; and S, ≤2/≤38; I, not available; R, ≥4/≥76)
‘Other non-Enterobacteriaceae', i.e. Pseudomonas spp. and other non-fastidious, glucose-non-fermenting gramnegative
bacilli, but excluding P. aeruginosa, Acinetobacter spp., Burkholderia cepacia, and S. maltophilia (disk,
not available; and S, ≥4/≤38; I, not available; R, ≥4/≥76)
Neisseria meningitidis (S, ≥30; I, 26-29; R, ≤25; and S, ≤0.12/≤2.4; I, 0.25/4.75; R, ≥0.5/≥9.5)
Resistance development/Cross-resistance

 

 

Resistance to Bactrim rarely develops during therapy. Cross-resistance exists among all
sulphonamides; cross-resistance to chemically unrelated antibiotics does not occur due to acquired
resistance to Bactrim.
Synergy/Antagonism
There is marked synergy between sulfamethoxazole and trimethoprim. This synergy usually exists
even when there is resistance to one of the two components.
Clinical Efficacy and safety
The clinical efficacy of Bactrim in the most commonly approved indications (see
"Indications/Uses") has been demonstrated in numerous clinical trials.
This applies in particular to prophylaxis of Pneumocystis jirovecii pneumonia (formerly known as
Pneumocystis carinii pneumonia, PCP) in HIV patients:
In a randomised study from the Netherlands with a median follow-up of one year, Bactrim Tablets
(80/400 mg) were compared with Bactrim forte Tablets (160/800 mg) in 260 HIV patients whose
CD4 cell count was below 200 cells/μl and who had not previously had PCP. None of the patients
in the two groups contracted PCP. There were more adverse effects requiring discontinuation of
TM-SMZ in the group treated with Bactrim forte (hazard ratio 1.4; 95% CI 0.95–2.02).
In a randomised multicentre study with a median follow-up period of almost two years, daily
administration of Bactrim forte Tablets was compared with three-times-weekly administration of
Bactrim forte Tablets in 2,625 HIV patients whose CD4 cell count was below 200 cells/μl and of
whom some had previously had PCP. In an intent-to-treat analysis, a similar annual PCP morbidity
rate was observed in both groups: 3.5 and 4.1 (relative risk 0.82; 95% CI 0.69–1.09). An ontreatment
analysis showed a lower risk of PCP when administered daily (relative risk 0.59; 95%
CI 0.37–0.95). Cessation of treatment with TM-SMZ due to adverse effects was more common
when administered daily (relative risk 2.14; 95% CI 1.73–2.66).

 

 

TM and SMZ largely overlap in their clinically relevant pharmacokinetic properties.
5.2.1 Absorption
TM and SMZ are rapidly and almost completely absorbed in the upper gastrointestinal tract after
oral administration (80%–100% bioavailability). After a single administration of 160 mg TM +
800 mg SMZ, peak plasma concentrations of 1.5–3 mg/l for TM and 40–80 mg/l for SMZ are
reached in 1 to 4 hours. With repeated administration, every twelve hours, the steady-state peak
plasma concentrations of SMZ and TM are usually 50%–100% higher than after single oral
administration. Plasma levels are dose-proportional. The influence of food on the kinetics of the
active components of Bactrim has not been investigated. After administration of a trimethoprim
suspension on a full stomach, the extent of absorption is less than after administration on an empty
stomach, but the rate of absorption was not changed by a standard meal.
5.2.2. Distribution
The distribution volume of TM is approx. 1.6 l/kg and of SMZ approx. 0.2 l/kg. TM is 37% and
SMZ 62% bound to plasma proteins. As animal studies and measurements on humans have shown,
tissue diffusion is favorable for Bactrim. TM passes very readily and SMZ to a lesser extent from
the bloodstream into the interstitial fluid and other extravascular body fluids. Concentrations of
TM and SMZ may be elevated in inflamed tissue. TM and SMZ have been detected in the fetal
placenta, cord blood, amniotic fluid and foetal tissues (liver, lungs), indicating that both substances
cross the placental barrier. In general, foetal TM concentrations are similar to those in maternal
blood, but those of SMZ are lower (see section 4.6 Fertility, pregnancy and lactation "). Both
substances are excreted into breast milk. Concentrations in breast milk are similar to (TM) or lower
(SMZ) than those in maternal plasma (see section 4.6 Fertility, pregnancy and lactation").
5.2.3 Metabolism
Metabolism accounts for 30% of total TM elimination. Based on the results of an in vitro study
conducted in human liver microsomes, the involvement of CYP3A4, CYP1A2 and CYP2C9 in the
oxidative metabolism of TM cannot be ruled out.

metabolites of TM are principally the 1- and 3-oxides as well as the 3'- and 4'-hydroxy
derivatives; some metabolites are active.
SMZ is 80% metabolised in the liver, mainly to its N4 acetyl derivative (≈ 40% of the administered
dose) and to a lesser extent by glucuronidation. SMZ is also degraded by oxidation. The first step
of oxidation, leading to the formation of the hydroxylamine derivative, is catalysed by CYP2C9;
the metabolites are inactive.
5.2.4. Elimination
In normal renal function, the half-lives of the two components are very similar (on average, ten
hours for TM and eleven hours for SMZ).
The total clearance is around 100 ml/min for TM and around 20 ml/min for SMZ.
The elimination half-life of TM is roughly half as long in children as in adults, while that of SMZ
is not significantly different.
Both substances and their metabolites are excreted mainly via the kidneys, both by glomerular
filtration and by tubular secretion. The concentration of TM in urine is roughly 100 times higher
than in plasma, while the concentration of SMZ is approximately five times higher.
Approximately two-thirds of the TM administered is excreted unchanged in urine. Depending on
the pH of the urine, 10–30% of a dose of SMZ is excreted unchanged in the urine.
The total plasma clearance of TM is equivalent to 1.9 ml/min/kg and that of SMZ to
0.32 ml/min/kg.
Renal clearance is 20–80 ml/min for trimethoprim and 1–5 ml/min for sulfamethoxazole.
Both substances are found in faeces to a small extent.
5.2.5. Pharmacokinetics in specific patient groups
Hepatic impairment
The pharmacokinetics of a single oral dose of TM-SMZ has been investigated in patients with
moderate (n = 4) or severe (n = 7) hepatic impairment and compared to that in healthy subjects
(n = 13). No significant differences in the pharmacokinetics of TM or SMZ have been found
between patients with renal dysfunction and healthy subjects, apart from prolongation of the
elimination half-life of TM by a maximum of twice the normal value in two patients with severe
liver damage.

Although there is no marked change in kinetics, especially for TM, in patients with hepatic
insufficiency, caution is nevertheless advised in patients with severe hepatic insufficiency during
treatment with high doses of Bactrim. For patients on haemodialysis, blood levels need to be
determined and dose adjustments are necessary.
Renal impairment
In patients with impaired kidney function, the elimination half-lives of both components are
prolonged; the dosage must be adjusted accordingly.
Intermittent or continuous ambulatory peritoneal dialysis has no significant effect on the
elimination of Bactrim. During haemodialysis and haemofiltration, considerable amounts of TM
and SMZ are removed. It is therefore recommended that the dose of Bactrim be increased by 50%
after each haemodialysis session. In children with renal insufficiency (CLcr < 30 ml/min),
clearance of TM is reduced and its elimination half-life prolonged. The TM-SMZ dosage in
paediatric patients with impaired renal function should be adjusted based on renal function (see
section 4.2 "Psology and method of administration, Patients with renal dysfunction").
Elderly patients
Owing to the importance of renal clearance in the TM elimination process and due to the fact that
creatinine clearance decreases physiologically with increasing age, a decrease in the renal
clearance and total body clearance of TM can be expected with age. The pharmacokinetics of SMZ
should be less affected by increasing age, as renal clearance of SMZ accounts for only 20% of
total SMZ clearance.
The dosage must be adjusted accordingly.
Children and adolescents
The results of various clinical pharmacokinetic studies conducted in the paediatric patient group
with normal renal function have confirmed that the pharmacokinetics of both Bactrim components,
TM and SMZ, is age-dependent in this patient group. Whilst elimination of TM-SMZ is reduced
in neonates in the first two months of life, TM and SMZ are eliminated more rapidly thereafter,
with greater total body clearance and a shorter elimination half-life. The differences are most
marked in infants (> 1.7 months to 24 months) and decrease with increasing age, compared to
toddlers (1 year to 3.6 years), children (7.5 years to < 10 years) and adults (see section 4.2
"Posology and method of administration ").

patients with mucoviscidosis
Renal clearance of TM and metabolic clearance of SMZ are increased in mucoviscidosis patients.
Hence, the total plasma clearance is increased and the elimination half-life decreased for both
active substances.

 

TM also inhibits folic acid reductase in mammalian cells, but many orders of magnitude higher
concentrations are required than in bacteria. Several studies have revealed that high doses of a
combination of TM and sulphonamides cause malformations and embryonic lethality in rats. Folic
acid antagonism appears to exist under these experimental conditions. However, the doses used
were 10 - 100 times higher than the therapeutic doses used in humans. TM is mutagenic in vitro.
SMZ produces thyroid carcinomas in rats. This finding appears to be species-specific and is
probably not clinically significant for humans.
Other information
Effects on diagnostic methods
Bactrim, in particular its component TM, may interfere with competitive protein binding assays
for methotrexate if bacterial dihydrofolate reductase is used as a binding protein. No interaction
occurs, however, when methotrexate is determined by radioimmunoassay. TM and SMZ can also
interfere with the Jaffé test (alkaline picrate acid reaction assay for creatinine), resulting in
overestimations of about 10% in the range of normal values.

Bactrim forte, Tablets
Dioctyl Sodium Sulfosuccinate
Magnesium Stearate
Sodium Starch Glycolate
Povidone 30

Not applicable.

Do not use this medicine after the expiry date ("EXP") stated on the container. Bactrim Forte tablets: 36 months (3 years).

Bactrim forte, Tablets:
Do not store above 25°C.
Keep out of the reach and sight of children

Bactrim Forte tablets 160 mg TM and 800 mg SMZ.
A white to almost white, oblong, biconvex tablet with one side plain and the other side with a
breakline tablet.
Each unit carton contains 10 tablets in 1 blister strip.
Not all pack sizes may be marketed

No special requirements.