Protrin Df Tab Product Monograph

INDICATIONS AND CLINICAL USE

PROTRIN (sulfamethoxazole and trimethoprim) has been effective in the treatment of infections associated with the following gram-positive and gram-negative organisms:

Gram-Negative Organisms

Haemophilus influenzae

Neisseria gonorrhoeae

Escherichia coli

Klebsiella species

Enterobacter (Aerobacter) aerogenes

Proteus mirabilis

Proteus vulgaris

Salmonella species

Shigella species

Vibrio cholerae

Gram-Positive Organisms

Streptococcus pyogenes

Streptococcus viridans

Staphylococcus albus

Staphylococcus aureus

Diplococcus pneumoniae

Other Organisms

Brucella melitensis

Nocardia asteroides

Nocardia brasiliensis

Paracoccidioides brasiliensis

Pneumocystis jiroveci

Streptomyces somaliensis

Sensitivity tests should be performed wherever possible to determine choice of therapy. These tests should be repeated if there is a failure to respond, relapse or early recurrence.

PROTRIN may be indicated for the following infections when caused by susceptible strains of the above organisms.

Urinary Tract Infections:

Treatment of acute uncomplicated urinary tract infections*. It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination.

Upper and Lower Respiratory Tract Infections:

Treatment of acute exacerbations of chronic bronchitis.

Treatment of Pneumocystis jiroveci pneumonia*. PROTRIN is also indicated in the treatment of infants and children with a diagnosis of Pneumocystis jiroveci pneumonitis, especially if they are immunosuppressed.

Gastrointestinal Tract Infections:

Treatment of cholera, as an adjunct to fluid and electrolyte replacement, when the organism has been shown to be sensitive in vitro.

Treatment of bacilliary dysentry*.

Other Infections:

Treatment of nocardiosis*. - Brucellosis (second line therapy), when used in combination with gentamicin or rifampicin.

PROTRIN is not indicated in infections associated with Pseudomonas, Mycoplasma, nor when the infection is caused by a virus.

This drug has not yet been fully evaluated in streptococcal infections. PROTRIN has been investigated clinically in these indications.

CONTRAINDICATIONS

PROTRIN (sulfamethoxazole and trimethoprim) is contraindicated in patients with a known hypersensitivity, including a history of drug-induced immune thrombocytopenia, in association with trimethoprim or sulfonamides, co-trimoxazole or any excipients of PROTRIN and in patients with documented megaloblastic anemia due to folate deficiency, evidence of marked liver parenchymal damage, or blood dyscrasias.

PROTRIN is contraindicated in patients with marked renal impairment where repeated serum assays cannot be carried out (see also PRECAUTIONS).

PROTRIN is contraindicated in pregnant patients and in nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus.

PROTRIN is contraindicated in infants less than two months of age.

WARNINGS

Fatalities associated with the administration of sulfonamides and PROTRIN although rare, have occurred due to severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), fulminant hepatic necrosis, agranulocytosis, aplastic anemia, other blood dyscrasias, and hypersensitivity of the respiratory tract.

PROTRIN (sulfamethoxazole and trimethoprim) should be discontinued at the first appearance of skin rash or any sign of adverse reaction. 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/or pulmonary infiltrates may be indicators of pulmonary hypersensitivity to sulfonamides which while rare, has been fatal. In rare instances a skin rash may be followed by more severe reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, or serious blood disorder. Complete blood counts should be done frequently in patients receiving sulfonamides.

PROTRIN should not be used in the treatment of streptococcal pharyngitis. Clinical studies have documented that patients with group A β-hemolytic streptococcal tonsillopharyngitis have a greater incidence of bacteriologic failure when treated with PROTRIN than to those patients treated with penicillin, as evidenced by failure to eradicate this organism from the tonsillopharyngeal area.

Rare life-threatening and fatal cases of immune thrombocytopenia have been reported with the use of sulfamethoxazole-trimethoprim.

PRECAUTIONS

General

PROTRIN should only be used where, in the judgement of the physician, the benefit of treatment outweighs any possible risks; consideration should be given to the use of a single effective antibacterial agent.

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

PROTRIN should be given with caution to patients with impaired renal or hepatic function, to those with possible folate deficiency (e.g., the elderly, chronic alcoholics, rheumatoid arthritics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states), and to those with severe allergy or bronchial asthma. Because of possible interference with folate metabolism, regular blood counts are advisable in these patients as well as patients who are on long term therapy. Changes indicative of folic acid impairment have, in certain specific situations, been reversed by folinic acid therapy.

A folate supplement should also be considered with prolonged high dosage of PROTRIN (see

Adverse Reactions).

In glucose-6-phosphate dehydrogenase-deficient individuals, hemolysis may occur. This reaction is frequently dose-related.

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

Caution should be exercised in administering trimethoprim to patients at risk of hyperkalemia and hyponatremia. Serum potassium and sodium and renal function should be closely monitored, and dosage should be adjusted for renal function (see Precautions, Renal Impairment and Dosage and Administration).

The risk factors for hyperkalemia are high trimethoprim dosage (20 mg/kg/day), renal insufficiency (serum creatinine ≥ 1.2 mg/dl), hypoaldosteronism, older age, dietary potassium and other drugs that impair potassium excretion. The likely mechanism is via trimethoprim inhibition of sodium channels in the distal nephron, similar to that of the potassium-sparing diuretic amiloride.

Hyperkalemia is generally reversible on discontinuation of trimethoprim. In patients presented with hyperkalemia due to PROTRIN, PROTRIN can be discontinued and appropriate standard potassium-lowering therapy instituted.

Except under careful supervision trimethoprim-sulfamethoxazole should not be given to patients with serious hematological disorders (See Adverse Reactions).

Functional inhibition of the renal tubular secretion of creatinine may produce a spurious fall in the estimated rate of creatinine clearance.

PROTRIN may affect the results of thyroid function tests but this is probably of little or no clinical significance.

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

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

Renal Impairment

In patients with renal impairment, a reduced or less frequent dosage is recommended in order to avoid accumulation of trimethoprim in the blood (see Dosage and 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. PROTRIN 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.

Use in the Elderly

There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, or concomitant use of other drugs. Severe skin reactions, or generalized bone marrow suppression (see WARNINGS and Adverse Reactions), 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 Dosage and Administration).

Close supervision is recommended when PROTRIN is used in elderly patients or in patients taking high doses of PROTRIN as these patients may be more susceptible to hyperkalemia and hyponatremia. Special care should be exercised when treating the elderly or suspected folate-deficient patients; folate supplementation should be considered.

Use in Children

PROTRIN is not recommended for pediatric patients younger than 2 months of age (see

CONTRAINDICATIONS).

Use in Pregnancy

Trimethoprim and sulfamethoxazole cross the placenta and their safety in human pregnancy has not been established. Trimethoprim is a folate antagonist and, in animal studies, both agents have been shown to cause fetal abnormalities. At doses in excess of the recommended human therapeutic dose, trimethoprim and sulfamethoxazole have been reported to cause cleft palate and other fetal abnormalities in rats, findings typical of a folate antagonist. Effects with trimethoprim were preventable by administration of dietary folate. In rabbits, fetal loss was seen at doses of trimethoprim in excess of human therapeutic doses. Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans. Therefore, PROTRIN should be avoided in pregnancy, particularly in the first trimester, unless the potential benefit to the mother outweighs the potential risk to the fetus; folate supplementation should be considered if PROTRIN is used in pregnancy.

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

Use in Nursing Mothers

Trimethoprim and sulfamethoxazole are excreted in breast milk. Administration of PROTRIN 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 PROTRIN should be avoided in infants younger than eight weeks in view of predisposition of young infants to hyperbilirubinaemia.

Patients with Special Diseases and Conditions

Use in the Treatment of and Prophylaxis for Pneumocystis jiroveci Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS):

The incidence of side effects, particularly rash, severe hypersensitivity reactions, fever, leukopenia, neutropenia, thrombocytopenia and elevated aminotransferase (transaminase)

values in AIDS patients who are being treated with PROTRIN for Pneumocystis jiroveci pneumonia (PJP) has been reported to be greatly increased compared with the incidence normally associated with the use of PROTRIN in non-AIDS patients. If signs of bone marrow depression occur, the patient should be given calcium folinate supplementation (5-10 mg/day).

The incidence of hyperkalemia and hyponatremia appears to be increased in AIDS patients receiving PROTRIN. Adverse effects are generally less severe in patients receiving PROTRIN for prophylaxis. A history of mild intolerance to PROTRIN in AIDS patients does not appear to predict intolerance of subsequent secondary prophylaxis. However, if a patient develops skin rash or any sign of adverse reaction, therapy with PROTRIN should be re-evaluated (see WARNINGS).

Rhabdomyolysis has been reported in HIV positive patients receiving trimethoprim-sulfamethoxazole for prophylaxis or treatment of PJP. 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 PROTRIN, sometimes after a dosage interval of a few days.

The concomitant use of leucovorin with PROTRIN for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study.

Phenylketonuric Patients

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

Drug-Food Interactions

Caution should be excercised in patients following potassium enriched dietary regimens.

Drug-Drug Interactions

In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with or without purpura has been reported.

Occasional reports suggest that patients receiving pyrimethamine at doses in excess of 25 mg weekly may develop megaloblastic anemia should PROTRIN be prescribed concurrently. In some situations, concomitant treatment with zidovudine may increase risk of hematological adverse reactions to PROTRIN If concomitant treatment is necessary, consideration should be given to monitoring of hematological parameters.

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

It has been reported that PROTRIN may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when PROTRIN is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.

PROTRIN may inhibit the hepatic metabolism of phenytoin. PROTRIN, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Close monitoring of the patient’s condition and serum phenytoin levels is advisable.

Sulfonamides can also displace methotrexate from plasma protein binding sites, thus increasing free methotrexate concentrations. Folate supplementation should be considered.

If PROTRIN is considered appropriate therapy in patients receiving other anti-folate drugs, a folate supplementation should be considered.

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

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

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

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

Concurrent use of rifampicin and PROTRIN results in a shortening of the plasma half life of trimethoprim after a period of about one week. This is not 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.

Laboratory Tests

Drug/Laboratory Test Interactions

PROTRIN, 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 Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

Information for Patients

Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation. Patients should tell their physician of all dietary regimens and supplements.

Adverse Reactions

The most common adverse effects are hyperkalemia, anorexia, monilial overgrowth, headache, gastrointestinal disturbances (nausea, vomiting, diarrhea) and allergic skin reactions (such as rash and urticaria). FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF

SULFONAMIDES AND PROTRIN ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE

REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL

NECROLYSIS (LYELL’S SYNDROME), FULMINANT HEPATIC NECROSIS,

AGRANULOCYTOSIS, APLASTIC ANEMIA, OTHER BLOOD DYSCRASIAS, AND

HYPERSENSITIVITY OF THE RESPIRATORY TRACT (SEE WARNINGS). Hematologic

Leukopenia, neutropenia, thrombocytopenia, megaloblastic anaemia, aplastic and hemolytic anemia, methemoglobinemia, purpura, agranulocytosis, hypoprothrombinemia, eosinophilia, haemolysis in certain susceptible G-6-PD deficient patients and bone marrow depression.

Allergic

Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), anaphylaxis, allergic myocarditis, erythema multiforme, toxicoderma, exfoliative dermatitis, angioedema, drug fever, chills, allergic vasculitis resembling Henoch-Schönlein 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.

Cardiovascular

QT prolongation

Hepatobiliary

Hepatitis, including cholestatic jaundice and hepatic necrosis, jaundice, elevation of serum transaminase, alkaline phosphatase and bilirubin. Hepatic changes including fatalities have been recorded in at-risk patients. Cholestatic jaundice and hepatic necrosis may be fatal.

Gastrointestinal

Pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, dry mouth, nausea, vomiting, pyrosis, gastric intolerance, gastritis or gastroenteritis, dyspepsia emesis, abdominal pain, constipation, flatulence, diarrhea.

Genitourinary

Impaired renal function (sometimes reported as renal failure), interstitial nephritis, kidney changes

(as indicated by abnormal elevations in blood urea nitrogen, blood non-protein nitrogen, serum creatinine and urine protein levels), toxic nephrosis with oliguria and anuria, crystalluria, hematuria, urgency, and dysuria.

Metabolic

Anorexia, hyperkalemia, hyponatremia, hypoglycemia (see also PRECAUTIONS).

Neurologic

Aseptic meningitis, convulsions, peripheral neuritis, ataxia, tremor, vertigo, tinnitus, headache.

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

Psychiatric

Hallucinations, depression, apathy, nervousness, dizziness.

Endocrine

The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Cross-sensitivity may exist with these agents.

Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides.

Musculoskeletal

Arthralgia, rhabdomyolysis and myalgia.

Respiratory System

Pulmonary infiltrates, cough, shortness of breath, dyspnea.

Miscellaneous

Weakness, fatigue, insomnia, vision troubles, alopecia, epistaxis, edema. Monilial overgrowth is common.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Acute

The amount of a single dose of PROTRIN (sulfamethoxazole and trimethoprim) 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 sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness, and unconsciousness. Pyrexia, hematuria, 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. General principles of treatment include the forcing oral fluids; 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. Inducing diuresis plus alkalinisation of urine will enhance the elimination of sulfamethoxazole. Alkalinisation will reduce the rate of 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 hemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole.

There is no known antidote for sulfonamide poisoning; however, calcium folinate (leucovorin), 3 to

6 mg I.M. for 5 to 7 days, is an effective antidote for adverse effects in the hemopoietic system caused by trimethoprim.

Chronic

Use of PROTRIN at high doses and/or for extended periods of time may cause confusion and bone marrow depression manifested as thrombocytopenia, leukopenia, and/or megaloblastic anemia. If signs of bone marrow depression occur, the patient should be given leucovorin; 5 to 15 mg leucovorin daily has been recommended by some investigators.

DOSAGE AND ADMINISTRATION

For Patients with Impaired Renal Function:

When renal function is impaired, a reduced dosage should be employed using the following table:

When only serum creatinine levels are known, the following formulae may be used t o estimate creatinine clearance. The serum creatinine must represent a steady state o f renal function:

Serious Systemic Infections

Children:

The recommended daily dosage for children is 5 to 10 mg trimethoprim/kg body weight/day and

25 to 50 mg sulfamethoxazole/kg body weight/day. Treatment should be continued until the patient has been symptom free for two days; the majority will require treatment for at least five days.

Other diseases, including certain tropical diseases rarely seen in Canada have also been successfully treated with PROTRIN. The duration of treatment is as follows:

Pneumocystis jiroveci Pneumonitis

Children and Adults

Therapy should be continued for a total treatment period of at least two weeks. The aim is to obtain peak plasma or serum levels of trimethoprim of greater than or equal to 5 micrograms/mL

(see Adverse Reactions)

Pharmaceutical Information

Drug Substance

The active ingredients of PROTRIN are a combination of trimethoprim and sulfamethoxazole which has been established in a ratio of 1:5.

Proper Name: Sulfamethoxazole

Chemical Name: N1-(5 - methyl - 3 - isoxazolyl) sulfanilamide

Structural Formula:

Molecular Formula: C10H11N3O3S

Molecular Weight: 253.31

Description: Sulfamethoxazole is a white to off-white, practically odourless, crystalline compound. It has a melting point of 167°C.

Proper Name: Trimethoprim

Chemical Name: 2,4 - diamino - 5 - (3,4,5 - trimethoxabenzyl) pimidine

Structural Formula:

Molecular Formula: C14H18N4O3

Molecular Weight: 290.32

Description: Trimethoprim is a white to cream, bitter crystalline powder. It has a melting point of 199-203°C and a solubility in water of 0.4 mg/mL.

Composition

Each PROTRIN - DF Tablet contains sulfamethoxazole , trimethoprim, and the following non-medicinal ingredients: methylcellulose, crosscarmellose sodium, magnesium stearate, and colloidal silicon dioxide.

Stability and Storage Recommendations

PROTRIN Tablets and Suspension should be stored at room temperature between 15° and

30°C and protected from light.

Availability of Dosage Forms

PROTRIN - DF Tablets: Each white, capsule-shaped tablet, one side scored and plain on the other side contains 800 mg sulfamethoxazole USP and 160 mg trimethoprirn USP. Available in bottles of 10, 100, 250 and 500.

Microbiology

PROTRIN (sulfamethoxazole and trimethoprim) is bactericidal in vitro against the gram-negative and gram-positive organisms listed in Table 3.

In vitro Activity: Trimethoprim is, in general, more active than sulfamethoxazole against most bacterial species (see Table 1). Notable exceptions to this include Neisseria gonorrhoeae and Pseudomonas aeruginosa (which is, in general, insensitive to these drugs)

Demonstration of Synergy

By testing trimethoprim and sulfamethoxazole, both separately and in combination, synergy can be demonstrated in vitro. Synergy is indicated by one or all of the following:

1. 1. by a reduction in the MIC of each drug when the drugs are used in combination
2. 2. by an increase in the size of the zone of inhibition around the combination disc; and
3. 3. by an increase in bactericidal activity when the drugs are used in combination

The reduction in the MIC varies with the ratio of the drugs present and it has been demonstrated that the optimum ratio, as measured by maximum reduction in the MIC's of both drugs, is that in which the drugs are present in proportions corresponding to their respective MIC when acting singly. It should be emphasized, however, that potentiation occurs over a wide range of ratios.

With an excess of one of the drugs, the proportion of the other drug may be markedly reduced below that of the optimum ratio, yet still produce a synergistic effect.

Table 1

COMPARISON OF ACTIVITY OF TRIMETHOPRIM AND SULFAMETHOXAZOLE

IN VITRO

The activities were compared in the Wellcome Nutrient Agar containing 5% lysed horse blood.

For Neisseria and Haemophilus spp., the medium was heated at 80°C for 5 minutes and in the case of Mycobacterium tuberculosis, Peizer and Schacter medium was used.

Figure 2

CONCENTRATION OF SULFAMETHOXAZOLE

CONCENTRATION OF SULFAMETHOXAZOLE: Isobologram showing the synergy existing between trimethoprim and sulfamethoxazole. Concentrations required to produce 50% inhibition of bacterial growth.

Because of the wide variation in sensitivities of organisms to trimethoprim and sulfamethoxazole, the optimum ratio is also variable and could be different for each organism. Since, in general, trimethoprim is about 20 to 100 times more active than sulfamethoxazole, when examining strains for enhanced susceptibility to the combination investigators have generally preferred to use a fixed ratio, choosing one near the modal optimum. The 1:20 ratio is used most frequently, and examples of the increase in activity are shown in Table 2.

Table 3 shows the consolidated reported incidence of sensitivity of 49 165 strains of 40 species to trimethoprim plus sulfamethoxazole from 28 studies. A standard sensitivity disc containing

1.25 μg trimethoprim and 23.75 μg sulfamethoxazole was used in each study, but the medium varied.

Effect of Sulfamethoxazole Resistance: (49)

A group of 449 clinical isolates were arbitrarily divided into two groups based on their respective sensitivities to sulfamethoxazole: resistant, MIC ≥, 100 ug/mL, and sensitive, MIC < 100 ug/mL.

These organisms were then tested against various concentrations of a fixed ratio of sulfamethoxazoletrimethoprim (16:l). Table 3 shows that the addition of trimethoprim significantly reduced the concentration of sulfamethoxazole required to inhibit most of the resistant organisms tested (except for Pseudomonas)

Table 3

INCIDENCE OF SENSITIVITY TO TRIMETHOPRIM + SULFAMETHOXAZOLE

S. aureus 4 929 4 280 86.8 S. epidermidis 99 83 83.8

D. pneumoniae 140 140 100.0

St. Pyogenes 757 699 92.3

St. viridans 873 803 91.9

Streptococci 191 102 53.4 St. agalactiae 20 20 100.0 Enterococci

Escherichia coli

7 394 18 903

3 798 16 851

51.4 89.1 Klebsiella 1 365 1 109 81.2

K. pneumoniae 12 12 100.0 Proteus spp. 3 142 2 436 77.5

Pr. vulgaris 610 402 65.9 Pr. mirabilis 2 730 2 337 85.6 Pr. morganii 183 160 87.4

Pr. rettgeri 498 431 86.5 Providence A 133 104 78.2

Klebs.-Enterobacter 670 458 68.4

Kl. edwardsii 2 2 100.0

Enterobacter 1 344 1 169 86.9

Ent. cloacae 193 187 96.9

Salmonella 594 586 98.6

Hafnia 92 82 89.1

Shigella 226 222 98.2 Sh. dysenteriae 12 8 66.7 Ps. aeruginosa 3 081 600 19.5 Ps. pseudomallei 12 6 50.0 Citrobacter 202 184 91.1 Serratia 28 26 92.9 Paracolobactrum 84 59 70.2

Haemophilus influenzae 284 218 76.8 Flavobacterium 2 2 100.0

Achromobacter 160 124 77.5 Arizona sp. 18 10 55.6 Alcaligenes sp. 150 127 84.7 AD group 4 4 100.0

Cory. diphtheriae 2 2 100.0

Acinetobacter 16 15 93.7

Aeromonas 4 4 100.0 Neisseria Meningitidis 6 6 100.0

Neisseria gonorrhoeae 32 31 97.0

The resistance of Bacteroides spp. and Lactobacilli is of special interest, for they comprise the major portion of the flora of the gut. Trimethoprim plus sulfamethoxazole given daily for 10 days to 12 adult volunteers, eliminated all members of the Enterobacteriaceae family from the feces but did not affect either of the former bacterial groups. This lack of effect of these major groups probably accounts for the infrequent occurrence of intestinal upsets during therapy with

PROTRIN.

Trimethoprim and Sulfonamide-Resistant Strains

The theoretical basis for the synergistic effect of PROTRIN is that sulfamethoxazole reduces the amount of dihydrofolate synthesized by the infecting organism (usually causing bacteriostasis), and an additional small amount of trimethoprim produces a complete block in the conversion of the folate to its active form (usually causing bacterial death).

When examined by conventional susceptibility methods, an organism is regarded as resistant to sulfonamides when its macroscopic growth is not affected. "Resistance" by this definition does not necessarily mean that the sulfonamide has not reduced the folate biosynthesis of the organism. There is indirect enzymatic evidence that the dihydrofolate content of such sulfonamide-resistant strains is, in fact, reduced in the presence of sulfonamides, although not to the same extent as that of sulfonamide-sensitive strains. Therefore, in the presence of sulfamethoxazole, the effect of trimethoprim on these sulfonamide-resistant strains should be increased because the amount of substrate against which the trimethoprim competes is reduced.

Streptococcus faecalis is often regarded as being indifferent to the presence of sulfonamides, yet the susceptibility of this organism (and of sulfonamide-resistant strains of Escherichia coli) can be shown to be enhanced markedly with the addition of trimethoprim. Perhaps even more convincing evidence can be obtained by the diffusion method.

Although sulfonamide sensitivity discs produce no zones of inhibition with Streptococcus faecalis, discs containing 23.75 μg sulfamethoxazole plus 1.25 μg trimethoprim produce larger zones of inhibited growth of Streptococcus faecalis than do discs containing 1.25 μg trimethoprim. The difference in size is abolished when para-aminobenzoic acid is present.

Reversal of Trimethoprim Activity

Trimethoprim acts by interfering with the conversion of dihydrofolic acid to tetrahydrofolic acid.

Therefore, the presence of an exogenous source of the latter should, theoretically, diminish or even abolish the antibacterial activity of PROTRIN in the host.

In vitro, 1 μg/mL folinic acid affects only the sensitivities of Streptococcus faecalis, an organism known to utilize exogenous folates. In vivo, when administered subcutaneously to mice infected with Diplococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Proteus vulgaris,

Salmonella schottmuelleri and Salmonella typhimurium, folinic acid does not affect the ability of trimethoprim to potentiate the antibacterial activity of sulfamethoxazole.

The in vitro interference with the action of trimethoprim and the sulfonamides by thymidine also raises the question of whether thymidine could affect in vivo activity. Experimental studies in the hamster indicate that thymidine is degraded rapidly in vivo. In experiments in mice where large doses of the nucleoside were given intraperitoneally, it did not interfere with the protection afforded by trimethoprim and sulfamethoxazole against Proteus vulgaris.

Resistance Development

During the serial passage in the presence of trimethoprim, little change in sensitivity occurs with light inocula; however, resistance develops rapidly with heavy inocula. With sulfonamide-sensitive strains, the emergence of these mutants is markedly delayed by the presence of sulfamethoxazole. The delaying effect of the sulfonamide depends, however, on the degree of sulfonamide resistance and is minimal with highly resistant strains.

Recently, R factors conferring high degrees of trimethoprim resistance have been identified in members of the Enterobacteriaceae family isolated from man and animals. A factor conferring high trimethoprim and sulfonamide resistance was detected in a strain of Escherichia coli and in a strain of Klebsiella aerogenes. Both strains were isolated from infected urine of human patients.

PHARMACOLOGY

The pharmacokinetic profiles of sulfamethoxazole and trimethoprim remain the same whether they are administered in combination or alone. Peak blood levels for both compounds occur one to four hours after oral administration. Detectable amounts are still present after 24 hours. The biological half-lives reported are 9-11 hours for sulfamethoxazole (26,39,50,51) and 10-14 hours for trimethoprim (26,50,51)

Serum binding (26)

In serum, the degree of protein-binding by trimethoprim varies with the concentration, but it normally is about 44% bound to plasma protein. Sulfamethoxazole was found to be about 70% bound to plasma protein. Addition of sulfamethoxazole reduced the binding of trimethoprim by

3 to 4%, but there was no change in the protein- binding of sulfamethoxazole at therapeutically attain able concentrations o f the two drugs (37,38).

Absorption

Both trimethoprim and sulfamethoxazole are rapidly absorbed following oral administration.

Detectable levels of both drugs appear in the blood in about five minutes with significant levels being reached within an hour. Peak blood levels for both compounds are attained usually in two to four hours, are maintained for about seven hours, and detectable amounts are still present after 24 hours. When the two drugs are administered together, the individual blood levels are similar to those achieved when the drugs are administered separately, thus indicating no effect in absorption of one drug by the other.

Distribution

The ratio of one part trimethoprim to five parts sulfamethoxazole achieves drug concentrations in the blood in the ratio of approximately 1:20, a ratio considered to be optimal against a wide range of bacteria. Unlike sulfamethoxazole, trimethoprim concentrates in tissues; biopsy material from a small number of patients taking trimethoprim preoperatively indicated that the concentration of trimethoprim in the tissues exceeded that of the plasma sampled at the same time - most significant in the lung (by 10 times). A similar pattern occurs in animals. Levels of trimethoprim in the sputum were also found to be higher than in the plasma following oral administration of trimethoprim-sulfamethoxazole. The concentrations of both drugs have also been found to be well-maintained in lymph and tissue fluids.

In serum, the degree of protein-binding by trimethoprim varies with the concentration, but it normally is about 44% bound to plasma protein. Sulfamethoxazole was found to be about 70% bound to plasma protein. Addition of sulfamethoxazole reduced the binding of trimethoprim by

3 to 4%, but there was no change in the protein-binding of sulfamethoxazole (about 66%) at therapeutically attainable concentrations of the two drugs.

Metabolism and Excretion

Studies conducted on the individual components administered separately, indicate that in the presence of a high fluid intake, approximately 50%, and in the presence of a low fluid intake, approximately 40% of the orally ingested trimethoprim is excreted unchanged in the urine within

24 hours. Approximately 10% of the excreted drug is in the form of metabolites with little or no antibacterial activity. Some trimethoprim is excreted in the bile, where concentrations twice those of plasma are obtained, but as it is almost completely reabsorbed; very little appears in the feces.

Studies with radio-labelled trimethoprim indicated that it is almost completely absorbed following oral administration in man; less than 4% of the radioactivity appeared in the feces over a period of six days. Radioactivity was eliminated from the plasma and urine at almost identical rates; almost all of an oral dose being excreted in the urine within 48 hours. The biological half-life of trimethoprim was calculated to be 10 hours (range of 6.2 to 12 hours in four patients), which corresponds well to the half-life of 9 to 11 hours determined in man for sulfamethoxazole. About 60% of the orally ingested sulfamethoxazole is excreted in the urine within 48 hours. Of the excreted drug, approximately half is the N⁴ acetylated derivative, a fifth is the N⁴ conjugate, a sixth is the unchanged parent compound, and about a tenth is another N⁴ free compound.

Although the amount of each drug excreted is similar when given separately or in combination, the method of excretion by the kidney is quite different. Sharpstone demonstrated that there is net tubular reabsorption of filtered sulfamethoxazole, at least in patients with normal renal function, whereas with trimethoprim there is a tubular secretory mechanism of excretion in patients with normal or impaired renal function.

Renal clearance of sulfamethoxazole increased with rising urine flow-rate, was independent of urine pH when this was less than 7, but increased with alkalinization of the urine above a pH of 7.

The clearance of trimethoprim was unaffected by alteration in urine flow-rate but increased sharply with falling urine pH.

In patients with impaired renal function, sulfamethoxazole excretion was only slightly decreased, whereas trimethoprim excretion decreased markedly in severe renal impairment.

Comparative Bioavailability Studies

Single-dose, standard two-way crossover bioavailability studies were performed using normal human volunteers.

A) The rate and extent of absorption of sulfamethoxazole and trimethoprim after a single oral dose of 800 mg of sulfamethoxazole and 160 mg of trimethoprim given as either one Bactrim

800-160 mg tablet or as one PROTRIN 800-160 mg tablet was measured and compared. The results can be summarized as follows: (36)

* SD = Standard Deviation

B) The rate and extent of absorption of sulfamethoxazole and trimethoprim after a single oral dose of 800 mg of sulfamethoxazole and 160 mg of trimethoprim given as either 20 mL of Bactrim

Suspension (200-40 mg/5 mL) or as 20 mL of PROTRIN Pediatric Suspension (200-40 mg/5 mL)

was measured and compared. The results can be summarized as follows:

* SD = Standard Deviation

TOXICOLGY

Acute Studies

Acute toxicity studies in rats of the separate components and of trimethoprim and

sulfamethoxazole combined in a ratio of 1:5 demonstrated the following LD50 values:

Subacute Studies

Daily dosages of 33, 100, and 300 mg/kg of trimethoprim and 133, 400, and 1200 mg/kg of sulfamethoxazole were given to young, sexually immature rhesus monkeys for one month. The compounds were also given in combination; the lower doses of each being combined, and similarly the higher ones. Effects on weight gain were seen. Loss in weight was noted with high and medium dosage groups with the combined drugs. Changes were induced in hemopoiesis which were consistent with trimethoprim action in interfering with dihydrofolate reductase activity.

Also high doses of the sulfonamide produce hypoplastic hemopoietic changes. Half the animals on high dose levels showed increased blood urea concentrations.

A similar study in rats produced similar results. In addition, some changes associated with the sulfonamide were noted in the thyroid and in the pituitary, such as increased weight and epithelial changes. Fatty changes were also seen in the liver of monkeys and rats on the medium and high dose levels.

Chronic Studies

Six Months

Toxicity studies of six months duration were conducted in rats and monkeys with a combination of trimethoprim and sulfamethoxazole (1:2 ratio) with total daily oral doses ranging between 99 and

900 mg/kg.

Doses of 99 mg/kg daily for six months were well-tolerated in both species with minimal signs of toxicity; 300 mg/kg was well-tolerated by monkeys, but in rats impaired growth was seen and 2 of the 10 animals in this dosage group died. With 900 mg/kg, marked effects on growth and on survival occurred in both species.

Histopathological examinations were made on more than 20 different tissues from each species;

these showed depression of hematopoiesis in both species in the 300 and 900 mg/kg dosage groups and minor changes with 99 mg/kg. These bone marrow changes were related to trimethoprim's interference with dihydrofolate reductase activity. Other tissue changes attributed to drug action seen in the rat, but not in the monkey, were thyroid hyperplasia and pituitary cytological effects, both associated with the sulfonamide moiety.

12-14 Months

Oral toxicity studies with trimethoprim and sulfamethoxazole, singly or in a 1:5 combination, were conducted in the monkey and in the rat. For the monkey, dose levels ranging from 10 + 50 to 60 +

300 mg/kg six days per week were employed for a period of 52 weeks; for the rat, dose levels ranging from 5 + 25 to 120 + 600 mg/kg per day were employed for a duration of 60 weeks. In the monkey, the 1:5 combination did not produce any significant compound-related effects, except for a slight reduction in weight gain in the 60 + 300 mg/kg dose group.

In the rat study, thyroid hyperplasia of a dose-related severity was seen after 13 weeks in all animals receiving sulfamethoxazole. This hyperplasia progressed to nodularity or adenoma formation in some rats after 52 weeks at doses as low as 50 mg/kg per day, and to local vascular invasion and lung metastases after 60 weeks at doses as low as 150 mg/kg per day. Pituitary changes (large pale cells, often vacuolated), considered to be secondary to the thyroid change, were found in a few rats in all the sulfamethoxazole treated groups.

The phenomenon of thyroid hyperplasia in rats has been produced in this species by a number of sulfonamides and antithyroid drugs. The thyroid hyperplasia which occurs under the influence of these drugs is considered to be compensatory to the failure of thyroid hormone synthesis; it has been stated that this hyperplasia can be prevented or reversed by thyroid hormone. The progression of thyroid hyperplasia to nodule or adenoma formation is an observation in rats which has been reported previously in the literature on the antithyroid drugs, thiouracil and thiourea. It is considered that in these studies the production of thyroid tumours was due, not to any direct carcinogenic action of the drugs, but rather to the excessive and prolonged stimulation of the thyroid epithelium by the thyrotropic secretion of the pituitary.

Other changes associated with sulfamethoxazole treatment in our animal studies were: a dose-related increased alkaline phosphatase, a dose-related reduction in mean body weight gain, slight depression of hematopoiesis, testicular atrophy, focal renal calcification, and slightly increased fat vacuolation of the liver and kidney.

Human Tolerance Studies

Chronic Tolerance and Toxicity Study

A double-blind, placebo-controlled trial designed to study human tolerance and possible toxic effects of an orally administered 1:5 trimethoprim/sulfamethoxazole combination, was completed in 36 normal healthy men for 13 weeks. At the two dose levels investigated (80 + 400 and 160 +

800 mg/kg three times daily) the drug appeared to be well-tolerated, with only a few minor, easily reversible side-effects occurring. The trial had to be stopped in two subjects due to recurrent black tongue.

Thyroid Function Study

Thyroid function tests (protein-bound iodine and serum cholesterol determinations) were conducted in 25 patients who received two to four PROTRIN Tablets daily for a duration of 35 to

760 days. In none of these patients was there evidence of depression of thyroid function. One patient showed a diffused stroma of the thyroid and an increased131I uptake, and another patient had a small diffused goiter after 120 days of treatment.

Reproduction and Teratology

A three-phase investigation, comprised of a fertility and general reproductive performance study and a perinatal and postnatal study in the rat, and teratology studies in the rat and rabbit, were conducted with an orally administered 1:5 combination of trimethoprim to sulfamethoxazole.

The dose levels investigated, singly or combined, were 70 + 350, 30 + 150, 15 + 75, 0 + 350, 0 +

150, 0 + 75, and 14 + 0 or 70 + 0 mg/kg.

Some drug-related effects noted in the investigation were: a reduced body weight gain by eight weeks in males in the Fertility and General Reproductive Performance Study at dose levels of

150 or 350 mg/kg of sulfamethoxazole, alone or in combination, and an increased incidence of maternal mortality in the rabbit teratology study at the same dose levels. In one of the 18 litters of the high combination group, four of the eight pups were abnormal. Two had bone malformations and two had curled tails, missing or small kidneys, absence of eyelid and one also had misshapen lateral ventricles of the brain. The instances of small, underdeveloped kidneys were such as to raise a question of dose relationships. In the teratogenicity study in rats, instances of small, underdeveloped kidneys were seen: in control group - 0; in combination groups (420 mg/kg dose) - 6 (8.5%), (180 mg/kg dose) - 3 (4.7%), (90 mg/kg dose) - 2 (3.2%). Other malformations noted in a group receiving 420 mg/kg, were one instance of incomplete nasal septum and two fetuses with abnormally large openings in the lateral ventricles. Fertility and general reproductive performance, and early and late fetal development were not affected by the dose regimen employed.

Fertility

In these studies, the animals were dosed per os with a 1:5 mixture of trimethoprim to sulfamethoxazole daily from 60 days before mating until the end of weaning.

In the rat, at 600 mg/kg there was a slight, non-significant lowering of the pregnancy rate when compared with controls. The number of live progeny per litter at birth and at weaning was less than in controls. A slight treatment-related disturbance of estrus and of sperm count was also noted.

With 200 mg/kg the pregnancy rate was slightly lower than in controls, but the other effects seen with the higher dose were not noted.

In the rabbit, daily oral doses of 600 mg/kg produced vomiting, even with divided doses, and was therefore abandoned. Two hundred mg/kg did not have a significant effect on the pregnancy rate, on the number of live births per litter, or on the mean weight of progeny at birth or at weaning.

Teratogenicity

In these studies, rats and rabbits were dosed by stomach tube daily from days 8 to 16 of pregnancy, or on a single day of pregnancy (rat only). Trimethoprim and sulfamethoxazole were used alone, in a 1:4 combination, and in a 1:2 combination.

For the rat, dosing with 500 mg/kg of trimethoprim on any single day of gestation between days 8 to 16 had no effect on the dams or their fetuses. A single dose of 2000 mg/kg of trimethoprim was lethal to most fetuses when given on the eighth or ninth day, and it produced a very high incidence of malformations when given on days 10, 11 or 12. However, the incidence of these malformations dropped off precipitately when dosing was on the 13th day or later.

The most common abnormality seen with either compound in the rat, when dosing was daily on days 8 to 16 of pregnancy, was cleft palate which occurred with 200 mg/kg of trimethoprim alone and with 640 mg/kg of sulfamethoxazole alone. Higher doses of trimethoprim produced bony defects and exencephaly, related to its action in interfering with dihydrofolate reductase activity.

The abnormalities could be prevented by the administration of folinic acid subcutaneously. No fetal abnormalities were found at daily doses of 160 mg/kg or less of trimethoprim, or 512 mg/kg or less of sulfamethoxazole. Using compounds in a 1:4 trimethoprim/ sulfamethoxazole combination, fetal malformations appeared at between 128 mg/kg and 160 mg/kg of trimethoprim and 512 mg/kg and 640 mg/kg of sulfamethoxazole. There appeared to be a distinct synergism with the 1 to 2 mixture.

In rabbits given the drug daily during organogenesis (days 8 to 16), no teratogenic effect was revealed with the 1:4 mixture or its components. While no important effect on the incidence of dead fetuses was noted with daily doses of 125 mg/kg of trimethoprim, 500 mg/kg or less of sulfamethoxazole, or with 312.5 mg/kg of the combination, the incidence of fetuses dying before full term was higher than for controls in the groups given trimethoprim except at the 62.5 mg/kg dose. Pregnant does tolerated the combination better than sulfamethoxazole alone.

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