Doctrim-DS

Pneumocystis Jirovecii Lungenentzündung

Doctrim-DS ist bei der Behandlung von angezeigt Pneumocystis jirovecii Lungenentzündung bei Erwachsenen und pädiatrischen Patienten ab zwei Monaten.

Shigellose

Doctrim-DS ist bei der Behandlung von Enteritis angezeigt, die durch anfällige Stämme von verursacht wird Shigella flexneri und Shigella sonnei bei Erwachsenen und pädiatrischen Patienten ab zwei Monaten.

Harnwegsinfektionen

Doctrim-DS ist bei der Behandlung schwerer oder komplizierter Harnwegsinfektionen bei Erwachsenen und pädiatrischen Patienten ab zwei Monaten aufgrund anfälliger Stämme von angezeigt Escherichia coli, Klebsiella Arten, Enterobacter Arten, Morganella Morganii und Proteus Arten, bei denen eine orale Verabreichung von Doctrim-DS nicht möglich ist und wenn der Organismus nicht anfällig für im Harntrakt wirksame antibakterielle Mittel mit einem Wirkstoff ist.

Verwendung

Um die Entwicklung arzneimittelresistenter Bakterien zu verringern und die Wirksamkeit von Doctrim-DS und anderen antibakteriellen Arzneimitteln aufrechtzuerhalten, sollte Doctrim-DS nur zur Behandlung oder Vorbeugung von Infektionen angewendet werden, bei denen nachgewiesen wurde oder der stark vermutet wird, dass sie durch anfällige Bakterien verursacht werden. Wenn Informationen zu Kultur und Anfälligkeit verfügbar sind, sollten sie bei der Auswahl oder Änderung der antibakteriellen Therapie berücksichtigt werden. In Ermangelung solcher Daten können lokale Epidemiologie- und Anfälligkeitsmuster zur empirischen Auswahl der Therapie beitragen.

Obwohl geeignete Kultur- und Anfälligkeitsstudien durchgeführt werden sollten, kann die Therapie begonnen werden, bis die Ergebnisse dieser Studien vorliegen.

Um die Entwicklung arzneimittelresistenter Bakterien zu verringern und die Wirksamkeit von Doctrim-DS und anderen antibakteriellen Arzneimitteln aufrechtzuerhalten, sollte Doctrim-DS nur zur Behandlung oder Vorbeugung von Infektionen angewendet werden, bei denen nachgewiesen wurde oder der stark vermutet wird, dass sie durch anfällige Bakterien verursacht werden. Wenn Informationen zu Kultur und Anfälligkeit verfügbar sind, sollten sie bei der Auswahl oder Änderung der antibakteriellen Therapie berücksichtigt werden. In Ermangelung solcher Daten können lokale Epidemiologie- und Anfälligkeitsmuster zur empirischen Auswahl der Therapie beitragen.

Harnwegsinfektionen

Zur Behandlung von Harnwegsinfektionen aufgrund anfälliger Stämme der folgenden Organismen: Escherichia coliKlebsiella Arten, Enterobacter Arten, Morganella MorganiiProteus mirabilis und Proteus vulgaris Es wird empfohlen, erste Episoden unkomplizierter Harnwegsinfektionen mit einem einzigen wirksamen antibakteriellen Mittel anstelle der Kombination zu behandeln.

Akute Otitis Media

Zur Behandlung von akuten Mittelohrentzündungen bei pädiatrischen Patienten aufgrund anfälliger Stämme von Streptococcus pneumoniae oder Haemophilus influenzae wenn Doctrim-DS nach Einschätzung des Arztes einen gewissen Vorteil gegenüber der Verwendung anderer antimikrobieller Mittel bietet. Bisher liegen nur begrenzte Daten zur Sicherheit der wiederholten Anwendung von Doctrim-DS bei pädiatrischen Patienten unter zwei Jahren vor. Doctrim-DS ist in keinem Alter für die prophylaktische oder verlängerte Verabreichung in Mittelohrentzündung angezeigt.

Akute Exazerbationen chronischer Bronchitis bei Erwachsenen

Zur Behandlung von akuten Exazerbationen chronischer Bronchitis aufgrund anfälliger Stämme von Streptococcus pneumoniae oder Haemophilus influenzae Wenn ein Arzt der Ansicht ist, dass Doctrim-DS einen gewissen Vorteil gegenüber der Verwendung eines einzelnen antimikrobiellen Mittels bieten könnte.

Durchfall der Reisenden bei Erwachsenen

Zur Behandlung von Reisedurchfall aufgrund anfälliger enterotoxigener Stämme E. coli.

Shigellose

Zur Behandlung von Enteritis, die durch anfällige Stämme von verursacht wird Shigella flexneri und Shigella sonnei wenn eine antibakterielle Therapie angezeigt ist.

Pneumocystis jiroveci Lungenentzündung

Zur Behandlung von dokumentiert Pneumocystis jiroveci Lungenentzündung. Zur Prophylaxe gegen Pneumocystis jiroveci Lungenentzündung bei Personen, die immunsupprimiert sind und ein erhöhtes Entwicklungsrisiko haben Pneumocystis jiroveci Lungenentzündung.

Septrin Pediatric Suspension ist zur Behandlung der folgenden Infektionen aufgrund empfindlicher Organismen indiziert:

Behandlung und Vorbeugung von Pneumocystis jiroveci (P. carinii) Pneumonitis

Behandlung und Prophylaxe von Toxoplasmose

Behandlung von Nocardiose

Die folgenden Infektionen können mit Septrin behandelt werden, wenn bakterielle Hinweise auf eine Empfindlichkeit gegenüber Septrin vorliegen und ein guter Grund besteht, die Kombination von Antibiotika in Septrin einem einzelnen Antibiotikum vorzuziehen:

Akute unkomplizierte Harnwegsinfektion

Akute Mittelohrentzündung

Akute Verschlimmerung der chronischen Bronchitis

Offizielle Leitlinien zur angemessenen Verwendung von antibakteriellen Wirkstoffen sollten berücksichtigt werden.

Dosage In Adults And Pediatric Patients (Two Months Of Age And Older)

The maximum recommended daily dose is 60 mL (960 mg trimethoprim) per day.

Table 1: Dosage in Adults and Pediatric Patients (Two Months of Age and Older) by Indication

Dosage Modifications In Patients With Impaired Renal Function

When renal function is impaired, a reduced dosage should be employed, as shown in Table 2.

Table 2: Impaired Renal Function Dosage Guidelines

Important Administration Instructions

Administer the solution by intravenous infusion over a period of 60 to 90 minutes. Avoid administration by rapid infusion or bolus injection. Do NOT administer Doctrim-DS intramuscularly.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever the solution and container permit.

Method Of Preparation

Dilution Of Single- And Multiple-Dose Vials

Doctrim-DS must be diluted. Each 5 mL should be added to 125 mL of 5% dextrose in water. After diluting with 5% dextrose in water, the solution should not be refrigerated and should be used within 6 hours.

If a dilution of 5 mL per 100 mL of 5% dextrose in water is desired, it should be used within 4 hours.

In those instances where fluid restriction is desirable, each 5 mL may be added to 75 mL of 5% dextrose in water. Under these circumstances the solution should be mixed just prior to use and should be administered within 2 hours.

If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and a fresh solution prepared.

Do NOT mix Doctrim-DS in 5% dextrose in water with drugs or solutions in the same container.

Multiple-Dose Vials (Handling)

After initial entry into the vial, the remaining contents must be used within 48 hours.

Infusion Systems For Intravenous Administration

The following infusion systems have been tested and found satisfactory: unit-dose glass containers; unit-dose polyvinyl chloride and polyolefin containers. No other systems have been tested and therefore no others can be recommended.

Doctrim-DS is contraindicated in pediatric patients less than 2 months of age.

Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients and Acute Otitis Media in Pediatric Patients

Adults

The usual adult dosage in the treatment of urinary tract infections is one Doctrim-DS DS (double strength) tablet, two Doctrim-DS tablets, or four teaspoonfuls (20 mL) Doctrim-DS Suspension every 12 hours for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of shigellosis.

Pediatric Patients

The recommended dose for pediatric patients with urinary tract infections or acute otitis media is 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole per 24 hours, given in two divided doses every 12 hours for 10 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. The following table is a guideline for the attainment of this dosage:

Pediatric Patients: Two Months of Age or Older

For Patients With Impaired Renal Function

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

Acute Exacerbations Of Chronic Bronchitis In Adults

The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is one Doctrim-DS DS (double strength) tablet, two Doctrim-DS tablets, or four teaspoonfuls (20 mL) Doctrim-DS Suspension every 12 hours for 14 days.

Travelers' Diarrhea In Adults

For the treatment of travelers' diarrhea, the usual adult dosage is one Doctrim-DS DS (double strength) tablet, two Doctrim-DS tablets, or four teaspoonfuls (20 mL) of Doctrim-DS Suspension every 12 hours for 5 days.

Pneumocystis jiroveci Pneumonia

Treatment

Adults And Pediatric Patients

The recommended dosage for treatment of patients with documented P jiroveci pneumonia is 15 to 20 mg/kg trimethoprim and 75 to 100 mg/kg sulfamethoxazole per 24 hours given in equally divided doses every 6 hours for 14 to 21 days. The following table is a guideline for the upper limit of this dosage:

For the lower limit dose (15 mg/kg trimethoprim and 75 mg/kg sulfamethoxazole per 24 hours) administer 75% of the dose in the above table.

Prophylaxis

Adults

The recommended dosage for prophylaxis in adults is one Doctrim-DS DS (double strength) tablet daily.

Pediatric Patients

For pediatric patients, the recommended dose is 150 mg/m /day trimethoprim 2 with 750 mg/m²/day sulfamethoxazole given orally in equally divided doses twice a day, on 3 consecutive days per week. The total daily dose should not exceed 320 mg trimethoprim and 1,600 mg sulfamethoxazole. The following table is a guideline for the attainment of this dosage in pediatric patients:

Method of administration: oral.

It may be preferable to take Septrin with some food or drink to minimise the possibility of gastrointestinal disturbances.

Standard dosage recommendations for acute infections

Children aged 12 years and under:

This dosage approximates to 6 mg trimethoprim and 30 mg sulfamethoxazole per kilogram body weight per 24 hours.

Treatment should be continued until the patient has been symptom free for two days; the majority will require treatment for at least 5 days. If clinical improvement is not evident after 7 days' therapy, the patient should be reassessed.

As an alternative to Standard Dosage for acute uncomplicated lower urinary tract infections, short-term therapy of 1 to 3 days' duration has been shown to be effective.

Special dosage recommendations

(Standard dosage applies unless otherwise specified)

Pneumocystis jiroveci (P. carinii) pneumonitis:

Treatment: A higher dosage is recommended using 20 mg trimethoprim and 100 mg sulfamethoxazole per kg of body weight per day in two or more divided doses for two weeks. The aim is to obtain peak plasma or serum levels of trimethoprim of greater than or equal to 5 microgram/ml (verified in patients receiving 1-hour infusions of intravenous Septrin). (See 4.8 Undesirable Effects).

Prevention:

The following dose schedules may be used for the duration of the period at risk (see Standard dosage recommendations for acute infections subsection of 4.2):

− Standard dosage taken in two divided doses, seven days per week

− Standard dosage taken in two divided doses, three times per week on alternate days

− Standard dosage taken in two divided doses, three times per week on consecutive days

− Standard dosage taken as a single dose, three times per week on consecutive days

The daily dose given on a treatment day approximates to 150 mg trimethoprim/m²/day and 750 mg sulfamethoxazole/m²/day. The total daily dose should not exceed 320 mg trimethoprim and 1600 mg sulfamethoxazole.

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

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

Children aged 12 years and under with renal impairment:

No data are available relating to dosage in children aged 12 years and under with impaired renal function.

Children aged 12 years and under with hepatic impairment:

No data are available relating to dosage in children aged 12 years and under with impaired hepatic function.

Doctrim-DS ist in folgenden Fällen kontraindiziert:

• Bekannte Überempfindlichkeit gegen Trimethoprim oder Sulfonamide
• Vorgeschichte einer medikamenteninduzierten Immunthrombozytopenie unter Verwendung von Trimethoprim und / oder Sulfonamiden
• Patienten mit dokumentierter megaloblastischer Anämie aufgrund von Folatmangel
• Pädiatrische Patienten unter zwei Monaten
• Markierter Leberschaden
• Schwere Niereninsuffizienz, wenn der Nierenfunktionsstatus nicht überwacht werden kann
• Gleichzeitige Anwendung mit Dofetilid2,3

Doctrim-DS ist bei Patienten mit bekannter Überempfindlichkeit gegen Trimethoprim oder Sulfonamide, bei Patienten mit medikamenteninduzierter Immunthrombozytopenie in der Vorgeschichte unter Verwendung von Trimethoprim und / oder Sulfonamiden sowie bei Patienten mit dokumentierter megaloblastischer Anämie aufgrund von Folatmangel kontraindiziert. Doctrim-DS ist bei pädiatrischen Patienten unter 2 Monaten kontraindiziert. Doctrim-DS ist auch bei Patienten mit ausgeprägter Leberschädigung oder schwerer Niereninsuffizienz kontraindiziert, wenn der Nierenfunktionsstatus nicht überwacht werden kann.

Septrin sollte nicht an Patienten mit Überempfindlichkeit gegen Sulfonamide, Trimethoprim, Co-Trimoxazol oder Hilfsstoffe von Septrin in der Vorgeschichte verabreicht werden.

Gegenanzeigen bei Patienten mit ausgeprägtem Leberparenchymschaden.

Gegenanzeigen bei schwerer Niereninsuffizienz, bei der wiederholte Messungen der Plasmakonzentration nicht durchgeführt werden können.

Septrin sollte in den ersten 6 Lebenswochen weder Frühgeborenen noch Vollzeitkindern verabreicht werden, mit Ausnahme der Behandlung / Prophylaxe von PCP bei Säuglingen ab 4 Wochen.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Embryo-Fetal Toxicity

Some epidemiologic studies suggest that exposure to Doctrim-DS during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If Doctrim-DS is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus.

Hypersensitivity And Other Fatal Reactions

Fatalities associated with the administration of sulfonamides, have occurred due to severe reactions, including, Stevens-Johnson Syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias.

Sulfonamides, including sulfonamide-containing products such as Doctrim-DS, 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. 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. Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.

Thrombocytopenia

Doctrim-DS-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Monitor patients for hematologic toxicity. Thrombocytopenia usually resolves within a week upon discontinuation of Doctrim-DS.

Streptococcal Infections And Rheumatic Fever

Avoid use of Doctrim-DS 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 Doctrim-DS than do those patients treated with penicillin, as evidenced by failure to eradicate this organism from the tonsillopharyngeal area. Therefore, Doctrim-DS will not prevent sequelae such as rheumatic fever.

Clostridium Difficile-Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Doctrim-DS, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Sulfite Sensitivity

Doctrim-DS contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

Benzyl Alcohol Toxicity In Pediatric Patients (“Gasping Syndrome”)

Doctrim-DS contains benzyl alcohol as a preservative. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved formulations in infusion solutions, including Doctrim-DS. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. Doctrim-DS is contraindicated in pediatric patients less than two months of age.

When prescribing Doctrim-DS in pediatric patients (two months of age and older), consider the combined daily metabolic load of benzyl alcohol from all sources including Doctrim-DS (contains 10 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol.

The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

Risk Associated With Concurrent Use Of Leucovorin For Pneumocystis Jirovecii Pneumonia

Treatment failure and excess mortality were observed when Doctrim-DS was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jirovecii pneumonia in a randomized placebo controlled trial.⁴ Avoid coadministration of Doctrim-DS and leucovorin during treatment of Pneumocystis jirovecii pneumonia.

Folate Deficiency

Avoid use of Doctrim-DS in patients with impaired renal or hepatic function, in those with possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states) and in those with severe allergies or bronchial asthma.

Hematologic changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure. These effects are reversible by folinic acid therapy.

Hemolysis

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

Infusion Reactions

Local irritation and inflammation due to extravascular infiltration of the infusion have been observed with Doctrim-DS. If these occur the infusion should be discontinued and restarted at another site.

Hypoglycemia

Cases of hypoglycemia in non-diabetic patients treated with Doctrim-DS have been seen, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of Doctrim-DS are particularly at risk.

Impaired Phenylalanine Metabolism

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

Porphyria And Hypothyroidism

Like other drugs containing sulfonamides, Doctrim-DS can precipitate porphyria crisis and hypothyroidism. Avoid use of Doctrim-DS in patients with porphyria or thyroid dysfunction.

Potential Risk In The Treatment Of Pneumocystis Jirovecii Pneumonia In Patients With Acquired Immunodeficiency Syndrome (AIDS)

AIDS patients may not tolerate or respond to Doctrim-DS in the same manner as non-AIDS patients. The incidence of adverse reactions, particularly rash, fever, leukopenia, and elevated aminotransferase (transaminase) values, with Doctrim-DS therapy in AIDS patients who are being treated for Pneumocystis jirovecii pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of Doctrim-DS in non-AIDS patients. If a patient develops skin rash or any sign of an adverse reaction, reevaluate therapy with Doctrim-DS.

Avoid coadministration of Doctrim-DS and leucovorin during treatment of Pneumocystis jirovecii pneumonia.

Electrolyte Abnormalities

High dosage of trimethoprim, as used in patients with P. jirovecii pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even treatment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly. Close monitoring of serum potassium is warranted in these patients.

Severe and symptomatic hyponatremia can occur in patients receiving Doctrim-DS, particularly for the treatment of P. jirovecii pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.

During treatment, ensure adequate fluid intake and urinary output to prevent crystalluria. Patients who are “slow acetylators” may be more prone to idiosyncratic reactions to sulfonamides.

Monitoring Of Laboratory Tests

Complete blood counts should be done frequently in patients receiving Doctrim-DS. Discontinue Doctrim-DS if a significant reduction in the count of any formed blood element is noted. Perform urinalyses with careful microscopic examination and renal function tests during therapy, particularly for those patients with impaired renal function.

Development Of Drug-Resistant Bacteria

Prescribing Doctrim-DS in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Sulfamethoxazole was not carcinogenic when assessed in a 26-week tumorigenic mouse (Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2-fold the human systemic exposure (at a daily dose of 800 mg sulfamethoxazole b.i.d. (twice a day).

Mutagenesis

In vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination. An in vitro chromosomal aberration test in human lymphocytes with sulfamethoxazole/trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole/trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole/trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities.

Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay and in in vitro micronucleus assays using cultured human lymphocytes.

Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in in vitro chromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation. In in vitro Comet, micronucleus and chromosomal damage assays using cultured human lymphocytes, trimethoprim was positive. In mice following oral administration of trimethoprim, no DNA damage in Comet assays of liver, kidney, lung, spleen, or bone marrow was recorded.

Impairment Of Fertility

No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim, doses roughly two times the recommended human daily dose on a body surface area basis.

Use In Specific Populations

Pregnancy

Risk Summary

Doctrim-DS may cause fetal harm if administered to a pregnant woman. Some epidemiologic studies suggest that exposure to Doctrim-DS during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot.

One of 3 rat studies showed cleft palate at doses approximately 5 times the recommended human dose on a body surface area basis; the other 2 studies did not show teratogenicity at similar doses. Studies in pregnant rabbits showed increased fetal loss at approximately 6 times the human dose on a body surface area basis.

The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Advise pregnant women of the potential harm of Doctrim-DS to the fetus.

Clinical Considerations

Disease-associated Maternal and/or Embryo/Fetal Risk

Urinary tract infection in pregnancy is associated with adverse perinatal outcomes such as preterm birth, low birth weight, and pre-eclampsia, and increased mortality to the pregnant woman. P. jirovecii pneumonia in pregnancy is associated with preterm birth and increased morbidity and mortality for the pregnant woman. Doctrim-DS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Data

Human Data

While there are no large, prospective, well-controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to Doctrim-DS with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons.

Alternatively, other epidemiologic studies did not detect statistically significant associations between Doctrim-DS exposure and specific malformations. Brumfitt and Pursell,¹⁰ in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or oral trimethoprim and sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester.

In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.

Animal Data

In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.

Lactation

Risk Summary

Levels of Doctrim-DS in breast milk are approximately 2 to 5% of the recommended daily dose for pediatric patients over two months of age. There is no information regarding the effect of Doctrim-DS on the breastfed infant or the effect on milk production. Because of the potential risk of bilirubin displacement and kernicterus on the breastfed child , advise women to avoid breastfeeding during treatment with Doctrim-DS.

Pediatric Use

Doctrim-DS is contraindicated in pediatric patients younger than two months of age because of the potential risk of bilirubin displacement and kernicterus.

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received benzyl alcohol as a preservative in infusion solutions. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

When prescribing Doctrim-DS in pediatric patients consider the combined daily metabolic load of benzyl alcohol from all sources including Doctrim-DS (Doctrim-DS contains 10 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

Geriatric Use

Clinical studies of Doctrim-DS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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, generalized bone marrow suppression , a specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients.

In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant Doctrim-DS therapy, especially in elderly patients. Serum digoxin levels should be monitored.

Hematologic changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions.

The trimethoprim component of Doctrim-DS may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of Doctrim-DS treatment is recommended to help lower potassium serum levels.

Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects.

REFERENCES

4. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. Oct 1994;170(4):912-7.

10. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov 1973;128 (Suppl): S657-S663.

WARNINGS

Embryofetal Toxicity

Some epidemiologic studies suggest that exposure to sulfamethoxazole/trimethoprim during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If sulfamethoxazole/trimethoprim is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus.

Hypersensitivity And Other Fatal Reactions

Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias.

PRECAUTIONS). Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions.

Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.

Thrombocytopenia

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

Streptococcal Infections And Rheumatic Fever

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

Clostridium Difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Doctrim-DS, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Adjunctive Treatment With Leucovorin For Pneumocystis jiroveci pneumonia

Treatment failure and excess mortality were observed when trimethoprim-sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jiroveci pneumonia in a randomized placebo controlled trial.⁷ Co-administration of trimethoprim-sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided.

PRECAUTIONS

Development Of Drug Resistant Bacteria

Prescribing Doctrim-DS in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Folate deficiency

Doctrim-DS 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, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states), and to those with severe allergy or bronchial asthma.

Hemolysis

In glucose-6-phosphate dehydrogenase-deficient individuals, hemolysis may occur. This reaction is frequently dose-related (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Hypoglycemia

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

Phenylalanine Metabolism

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

Porphyria And Hypothyroidism

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

Use In The Treatment Of And Prophylaxis For Pneumocystis jiroveci Pneumonia In Patients With Acquired Immunodeficiency Syndrome (AIDS)

AIDS patients may not tolerate or respond to Doctrim-DS it the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, leukopenia, and elevated aminotransferase (transaminase) values in AIDS patients who are being treated with Doctrim-DS for P. jiroveci pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of Doctrim-DS in non-AIDS patients. Adverse effects are generally less severe in patients receiving Doctrim-DS for prophylaxis. A history of mild intolerance to Doctrim-DS 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 Doctrim-DS should be re-evaluated (see WARNINGS).

Co-administration of Doctrim-DS and leucovorin should be avoided with P. jiroveci pneumonia (see WARNINGS).

Electrolyte Abnormalities

High dosage of trimethoprim, as used in patients with P. jiroveci pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even treatment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly. Close monitoring of serum potassium is warranted in these patients.

Severe and symptomatic hyponatremia can occur in patients receiving sulfamethoxazole/trimethoprim, particularly for the treatment of P. jiroveci pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.

During treatment, adequate fluid intake and urinary output should be ensured to prevent crystalluria. Patients who are “slow acetylators” may be more prone to idiosyncratic reactions to sulfonamides.

Laboratory Tests

Complete blood counts should be done frequently in patients receiving Doctrim-DS; if a significant reduction in the count of any formed blood element is noted, Doctrim-DS should be discontinued. Urinalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Sulfamethoxazole was not carcinogenic when assessed in a 26-week tumorigenic mouse (Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2.4-fold the human systemic exposure (at a daily dose of 800 mg sulfamethoxazole b.i.d.).

Mutagenesis

In vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination. An in vitro chromosomal aberration test in human lymphocytes with sulfamethoxazole/trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole/trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole/trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities.

Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay and in in vitro micronucleus assays using cultured human lymphocytes.

Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in in vitro chromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation. In in vitro Comet, micronucleus and chromosomal damage assays using cultured human lymphocytes, trimethoprim was positive. In mice following oral administration of trimethoprim, no DNA damage in Comet assays of liver, kidney, lung, spleen, or bone marrow was recorded.

Impairment Of Fertility

No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 70 mg/kg/day trimethoprim plus 350 mg/kg/day sulfamethoxazole, doses roughly two times the recommended human daily dose on a body surface area basis.

Pregnancy

While there are no large, well-controlled studies on the use of trimethoprim and sulfamethoxazole in pregnant women, Brumfitt and Pursell,⁹ in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or trimethoprim and sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.

Because trimethoprim and sulfamethoxazole may interfere with folic acid metabolism, Doctrim-DS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects

Pregnancy Category D

Human Data

While there are no large prospective, well controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to sulfamethoxazole/trimethoprim with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons. Alternatively, other epidemiologic studies did not detect statistically significant associations between sulfamethoxazole/trimethoprim exposure and specific malformations.

Animal Data

In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.

Nonteratogenic Effects

See CONTRAINDICATIONS section.

Nursing Mothers

Levels of trimethoprim/sulfamethoxazole in breast milk are approximately 2-5% of the recommended daily dose for infants over 2 months of age. Caution should be exercised when Doctrim-DS is administered to a nursing woman, especially when breastfeeding jaundiced, ill, stressed, or premature infants because of the potential risk of bilirubin displacement and kernicterus.

Pediatric Use

Doctrim-DS is contraindicated for pediatric patients younger than 2 months of age (see INDICATIONS AND USAGE and CONTRAINDICATIONS).

Geriatric Use

Clinical studies of Doctrim-DS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), a specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant Doctrim-DS therapy, especially in elderly patients. Serum digoxin levels should be monitored. Hematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions (see DOSAGE AND ADMINISTRATION section). The trimethoprim component of Doctrim-DS may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors.⁸ Close monitoring of serum potassium is warranted in these patients. Discontinuation of Doctrim-DS treatment is recommended to help lower potassium serum levels. Doctrim-DS Tablets contain 1.8 mg (0.08 mEq) of sodium per tablet. Doctrim-DS DS Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet.

Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimpethoprim was lower in geriatric subjects compared with younger subjects³ (see CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics:).

REFERENCES

3. Varoqaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly. Br J Clin Pharmacol. 1985; 20: 575-581.

7. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994 Oct; 170(4): 912-7.

8. Marinella MA. Trimethoprim - induced hyperkalemia: An analysis of reported cases. Gerontology 45: 209-212, 1999.

9. Brumfitt W, Pursell R. Trimethoprim-sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis. 1973;128 (suppl):S657-S663.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patients with rare hereditary problems of fructose intolerance should not take this medicine. See Section 2 Quantitative and Qualitative Composition.

This medicinal product contains methyl hydroxybenzoate, which may cause allergic reactions (possibly delayed).

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 5 ml.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.

The following serious adverse reactions are described elsewhere in the labeling:

• Embryo-fetal Toxicity
• Hypersensitivity and Other Fatal Reactions
• Thrombocytopenia
• Clostridium difficile-Associated Diarrhea
• Sulfite Sensitivity
• Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia
• Infusion Reactions
• Hypoglycemia
• Electrolyte Abnormalities

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions are gastrointestinal disturbances (nausea, vomiting, and anorexia) and allergic skin reactions (such as rash and urticaria).

Local reaction, pain and slight irritation on intravenous (IV) administration are infrequent. Thrombophlebitis has been observed.

Table 3: Adverse Reactions Reported with Doctrim-DS

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Doctrim-DS. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

• Thrombotic thrombocytopenia purpura
• Idiopathic thrombocytopenic purpura
• QT prolongation resulting in ventricular tachycardia and torsade de pointes

The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA, OTHER BLOOD DYSCRASIAS, AND HYPERSENSITIVITY OF THE RESPIRATORY TRACT (SEE WARNINGS).

Hematologic

Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia.

Allergic

Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch- Schonlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria, and rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported.

Gastrointestinal

Hepatitis, including cholestatic jaundice and hepatic necrosis, elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia.

Genitourinary

Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, crystalluria, and nephrotoxicity in association with cyclosporine.

Metabolic

Hyperkalemia, hyponatremia (see PRECAUTIONS: Electrolyte Abnormalities).

Neurologic

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

Psychiatric

Hallucinations, depression, apathy, nervousness.

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 and myalgia. Cases of rhabdomyolysis have been reported with Doctrim-DS, mainly in AIDS patients.

Respiratory System

Cough, shortness of breath, and pulmonary infiltrates (see WARNINGS).

Miscellaneous

Weakness, fatigue, insomnia.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of trimethoprim-sulfamethoxazole. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

• Thrombotic thrombocytopenia purpura
• Idiopathic thrombocytopenic purpura
• QT prolongation resulting in ventricular tachycardia and torsade de pointes

Prevention:

The following dose schedules may be used for the duration of the period at risk (see Standard dosage recommendations for acute infections subsection of 4.2):

− Standard dosage taken in two divided doses, seven days per week

− Standard dosage taken in two divided doses, three times per week on alternate days

− Standard dosage taken in two divided doses, three times per week on consecutive days

− Standard dosage taken as a single dose, three times per week on consecutive days

The daily dose given on a treatment day approximates to 150 mg trimethoprim/m²/day and 750 mg sulfamethoxazole/m²/day. The total daily dose should not exceed 320 mg trimethoprim and 1600 mg sulfamethoxazole.

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

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

Children aged 12 years and under with renal impairment:

No data are available relating to dosage in children aged 12 years and under with impaired renal function.

Children aged 12 years and under with hepatic impairment:

No data are available relating to dosage in children aged 12 years and under with impaired hepatic function.

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

Contra-indicated in patients showing marked liver parenchymal damage.

Contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

Septrin should not be given to premature babies nor to full-term infants during the first 6 weeks of life except for the treatment/prophylaxis of PCP in infants 4 weeks of age or greater.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patients with rare hereditary problems of fructose intolerance should not take this medicine. See Section 2 Quantitative and Qualitative Composition.

This medicinal product contains methyl hydroxybenzoate, which may cause allergic reactions (possibly delayed).

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 5 ml.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.

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

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

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

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

When trimethoprim is administered simultaneously with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. procainamide, amantadine), there is the possibility of competitive inhibition of this process which may lead to an increase in plasma concentration of one or both of the drugs.

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

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

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

Co-trimoxazole prolongs the half-life of phenytoin and if co-administered could result in excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels are advisable.

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

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

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

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

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

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

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

Pregnancy

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

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

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

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

Lactation

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

There have been no studies to investigate the effect of Septrin on driving performance or the ability to operate machinery. Further a detrimental effect on such activities cannot be predicted from the pharmacology of the drug. Nevertheless the clinical status of the patient and the adverse events profile of Septrin should be borne in mind when considering the patients ability to operate machinery.

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

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

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

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

Acute

Since there has been no extensive experience in humans with single doses of Doctrim-DS in excess of 25 mL (400 mg trimethoprim and 2000 mg sulfamethoxazole), the maximum tolerated dose in humans is unknown.

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 administration of intravenous fluids if urine output is low and renal function is normal. Acidification of the urine will increase renal elimination of trimethoprim. The patient should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole.

Chronic

Use of Doctrim-DS at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia. If signs of bone marrow depression occur, the patient should be given leucovorin 5 to 15 mg daily until normal hematopoiesis is restored.

Acute

The amount of a single dose of Doctrim-DS 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 institution of gastric lavage or emesis; 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. 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.

Chronic

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

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

If vomiting has not occurred, induction of vomiting may be desirable. Gastric lavage may be useful, though absorption from the gastrointestinal tract is normally very rapid and complete within approximately two hours. This may not be the case in gross overdosage. Dependant on the status of renal function administration of fluids is recommended if urine output is low.

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

Nach einer 1-stündigen intravenösen Infusion einer Einzeldosis von 160 mg Trimethoprim und 800 mg Sulfamethoxazol an 11 Patienten mit einem Gewicht zwischen 105 lbs und 165 lbs (bedeuten, 143 lbs) Die maximalen Plasmakonzentrationen von Trimethoprim und Sulfamethoxazol betrugen 3,4 ± 0,3 μg / ml und 46,3 ± 2,7 μg / ml, beziehungsweise. Nach wiederholter intravenöser Verabreichung derselben Dosis in Abständen von 8 Stunden, Die mittleren Plasmakonzentrationen unmittelbar vor und unmittelbar nach jeder Infusion im stationären Zustand betrugen 5,6 ± 0,6 μg / ml und 8,8 ± 0,9 μg / ml für Trimethoprim und 70,6 ± 7,3 μg / ml und 105,6 ± 10,9 μg / ml für Sulfamethoxazol. Die mittlere Plasma-Halbwertszeit betrug 11,3 ± 0,7 Stunden für Trimethoprim und 12,8 ± 1,8 Stunden für Sulfamethoxazol. Alle diese 11 Patienten hatten eine normale Nierenfunktion und ihr Alter lag zwischen 17 und 78 Jahren (Median, 60 Jahre).¹¹

Pharmakokinetische Studien bei Kindern und Erwachsenen legen eine altersabhängige Halbwertszeit von Trimethoprim nahe, wie in Tabelle 5 angegeben. ¹²

Tabelle 5: Halbwertszeit von Trimethoprim (TMP) bei pädiatrischen Patienten und Erwachsenen

Patienten mit stark eingeschränkter Nierenfunktion weisen eine Erhöhung der Halbwertszeiten beider Komponenten auf, was eine Anpassung des Dosierungsschemas erfordert.

Verteilung

Sowohl Trimethoprim als auch Sulfamethoxazol existieren im Blut als ungebundene, proteingebundene und metabolisierte Formen; Sulfamethoxazol existiert auch als konjugierte Form.

Ungefähr 44% von Trimethoprim und 70% von Sulfamethoxazol sind an Plasmaproteine gebunden. Das Vorhandensein von 10 mg Prozent Sulfamethoxazol im Plasma verringert die Proteinbindung von Trimethoprim in unbedeutendem Maße. Trimethoprim beeinflusst die Proteinbindung von Sulfamethoxazol nicht.

Sowohl Trimethoprim als auch Sulfamethoxazol verteilen sich auf Sputum und Vaginalflüssigkeit. Trimethoprim verteilt sich auch auf Bronchialsekrete, und beide passieren die Plazentaschranke und werden in die Muttermilch ausgeschieden.

Beseitigung

Stoffwechsel

Sulfamethoxazol wird beim Menschen zu mindestens 5 Metaboliten metabolisiert: dem N₄-acetyl-, N₄-hydroxy-, 5methylhydroxy-, N₄-acetyl-5-methylhydroxy-sulfamethoxazol-Metaboliten und ein N-Glucuronid-Konjugat. Die Bildung von N₄-Hydroxymetabolit wird über CYP2C9 vermittelt.

Trimethoprim wird metabolisiert in vitro zu 11 verschiedenen Metaboliten, von denen fünf Glutathionaddukte und sechs oxidative Metaboliten sind, einschließlich der Hauptmetaboliten 1- und 3-Oxide sowie der 3- und 4-Hydroxyderivate.

Die freien Formen von Trimethoprim und Sulfamethoxazol gelten als therapeutisch aktive Formen. In vitro Studien legen nahe, dass Trimethoprim ein Substrat von P-Glykoprotein, OCT1 und OCT2 ist und dass Sulfamethoxazol kein Substrat von P-Glykoprotein ist.

Ausscheidung

Die Ausscheidung von Trimethoprim und Sulfamethoxazol erfolgt hauptsächlich über die Nieren sowohl durch glomeruläre Filtration als auch durch tubuläre Sekretion. Die Urinkonzentrationen von Trimethoprim und Sulfamethoxazol sind erheblich höher als die Konzentrationen im Blut. Der Prozentsatz der Dosis, die über einen Zeitraum von 12 Stunden nach intravenöser Verabreichung der ersten Dosis von 240 mg Trimethoprim und 1200 mg Sulfamethoxazol am Tag 1 im Urin ausgeschieden wurde, lag zwischen 17% und 42,4% als freies Trimethoprim; 7% bis 12,7% als freies Sulfamethoxazol; und insgesamt 36,7% bis 56% (frei plus der N4-acetylierte Metabolit) Sulfamethoxazol. Bei gemeinsamer Verabreichung als Doctrim-DS beeinflussen weder Trimethoprim noch Sulfamethoxazol das Urinausscheidungsmuster des anderen.

REFERENZEN

3. Varoqaux O et al. Pharmakokinetik der Trimethoprim-Sulfamethoxazol-Kombination bei älteren Menschen. Br J Clin Pharmacol. 1985; 20: 575 & ndash; 581.

7. Safrin S, Lee BL, Sande MA. Adjunktive Folinsäure mit Trimethoprim-Sulfamethoxazol bei Pneumocystis carinii-Pneumonie bei AIDS-Patienten ist mit einem erhöhten Risiko für therapeutisches Versagen und Tod verbunden. J Infect Dis. 1994 Okt; 170 (4): 912 & ndash; 7.

8. Marinella MA. Trimethoprim - induzierte Hyperkaliämie: Eine Analyse der gemeldeten Fälle. Gerontology 45: 209 & ndash; 212, 1999.

9. Brumfitt W, Pursell R. Trimethoprim-Sulfamethoxazol bei der Behandlung von Bakteriurie bei Frauen. J Infect Dis. 1973; 128 (Suppl): S657-S663.

ÜBERDOSE

Akut

Die Menge einer Einzeldosis Doctrim-DS, die entweder mit Symptomen einer Überdosierung verbunden ist oder wahrscheinlich lebensbedrohlich ist, wurde nicht berichtet. Anzeichen und Symptome einer Überdosierung mit Sulfonamiden sind Anorexie, Kolik, Übelkeit, Erbrechen, Schwindel, Kopfschmerzen, Schläfrigkeit und Bewusstlosigkeit. Pyrexie, Hämaturie und Kristallurie können festgestellt werden. Blutdyskrasien und Gelbsucht sind mögliche späte Manifestationen einer Überdosierung. Anzeichen einer akuten Überdosierung mit Trimethoprim sind Übelkeit, Erbrechen, Schwindel, Kopfschmerzen, psychische Depressionen, Verwirrung und Knochenmarkdepression.

Allgemeine Behandlungsprinzipien sind die Einrichtung von Magenspülung oder Erbrechen; Erzwingen oraler Flüssigkeiten; und die Verabreichung von intravenösen Flüssigkeiten, wenn der Urinausstoß gering und die Nierenfunktion normal ist. Die Versauerung des Urins erhöht die renale Elimination von Trimethoprim. Der Patient sollte mit Blutbild und geeigneten Blutchemien, einschließlich Elektrolyten, überwacht werden. Wenn eine signifikante Blutdyskrasie oder Gelbsucht auftritt, sollte eine spezifische Therapie für diese Komplikationen eingeleitet werden. Peritonealdialyse ist nicht wirksam und Hämodialyse ist nur mäßig wirksam bei der Eliminierung von Trimethoprim und Sulfamethoxazol.

Chronisch

Die Verwendung von Doctrim-DS in hohen Dosen und / oder über längere Zeiträume kann eine Knochenmarkdepression verursachen, die sich als Thrombozytopenie, Leukopenie und / oder megaloblastische Anämie manifestiert. Wenn Anzeichen einer Knochenmarkdepression auftreten, sollte dem Patienten Leukovorin verabreicht werden. Einige Forscher haben täglich 5 bis 15 mg Leukovorin empfohlen.

KONTRAINDIKATIONEN

Doctrim-DS ist bei Patienten mit bekannter Überempfindlichkeit gegen Trimethoprim oder Sulfonamide, bei Patienten mit medikamenteninduzierter Immunthrombozytopenie in der Vorgeschichte unter Verwendung von Trimethoprim und / oder Sulfonamiden sowie bei Patienten mit dokumentierter megaloblastischer Anämie aufgrund von Folatmangel kontraindiziert. Doctrim-DS ist bei pädiatrischen Patienten unter 2 Monaten kontraindiziert. Doctrim-DS ist auch bei Patienten mit ausgeprägter Leberschädigung oder schwerer Niereninsuffizienz kontraindiziert, wenn der Nierenfunktionsstatus nicht überwacht werden kann.

KLINISCHE PHARMAKOLOGIE

Doctrim-DS wird nach oraler Verabreichung schnell resorbiert. Sowohl Sulfamethoxazol als auch Trimethoprim existieren im Blut als ungebundene, proteingebundene und metabolisierte Formen; Sulfamethoxazol existiert auch als konjugierte Form.. Sulfamethoxazol wird beim Menschen zu mindestens 5 Metaboliten metabolisiert: den N4-Acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl-5-methylhydroxysulfamethoxazol-Metaboliten und einem N-Glucuronid-Konjugat. Die Bildung von N4-Hydroxy-Metaboliten wird über CYP2C9 vermittelt.

Trimethoprim wird in vitro zu 11 verschiedenen Metaboliten metabolisiert, von denen fünf Glutathionaddukte und sechs oxidative Metaboliten sind, einschließlich der Hauptmetaboliten 1- und 3-Oxide sowie der 3- und 4-Hydroxyderivate.

Die freien Formen von Sulfamethoxazol und Trimethoprim gelten als therapeutisch aktive Formen. In-vitro-Studien legen nahe, dass Trimethoprim ein Substrat von P-Glykoprotein, OCT1 und OCT2 ist und dass Sulfamethoxazol kein Substrat von Pglykoprotein ist.

Ungefähr 44% von Trimethoprim und 70% von Sulfamethoxazol sind an Plasmaproteine gebunden. Das Vorhandensein von 10 mg Prozent Sulfamethoxazol im Plasma verringert die Proteinbindung von Trimethoprim in unbedeutendem Maße. Trimethoprim beeinflusst die Proteinbindung von Sulfamethoxazol nicht.

Spitzenblutspiegel für die einzelnen Komponenten treten 1 bis 4 Stunden nach oraler Verabreichung auf. Die mittleren Serumhalbwertszeiten von Sulfamethoxazol und Trimethoprim betragen 10 bzw. 8 bis 10 Stunden. Patienten mit stark eingeschränkter Nierenfunktion weisen jedoch einen Anstieg der Halbwertszeiten beider Komponenten auf, was eine Anpassung des Dosierungsschemas erfordert (siehe DOSIERUNG UND VERWALTUNG). 24 Stunden nach der Verabreichung des Arzneimittels sind nachweisbare Mengen an Trimethoprim und Sulfamethoxazol im Blut vorhanden. Während der Verabreichung von 160 mg Trimethoprim und 800 mg Sulfamethoxazol b.i.d.Die mittlere Steady-State-Plasmakonzentration von Trimethoprim betrug 1,72 µg / ml. Die stationären minimalen Plasmaspiegel von freiem und vollständigem Sulfamethoxazol betrugen 57,4 µg / ml bzw. 68,0 µg / ml. Diese Steady-State-Spiegel wurden nach 3 Tagen Arzneimittelverabreichung erreicht.¹

Die Ausscheidung von Sulfamethoxazol und Trimethoprim erfolgt hauptsächlich über die Nieren sowohl durch glomeruläre Filtration als auch durch tubuläre Sekretion. Die Urinkonzentrationen von Sulfamethoxazol und Trimethoprim sind erheblich höher als die Konzentrationen im Blut. Der durchschnittliche Prozentsatz der im Urin von 0 bis 72 Stunden nach einer oralen Einzeldosis zurückgewonnenen Dosis beträgt 84,5% für Gesamtsulfonamid und 66,8% für freie Trimethoprim. Dreißig Prozent des gesamten Sulfonamids werden als freies Sulfamethoxazol ausgeschieden, der Rest ist N-acetylierter Metabolit.² Bei gemeinsamer Verabreichung als Doctrim-DS beeinflussen weder Sulfamethoxazol noch Trimethoprim das Urinausscheidungsmuster des anderen.

Sowohl Trimethoprim als auch Sulfamethoxazol verteilen sich auf Sputum, Vaginalflüssigkeit und Mittelohrflüssigkeit. Trimethoprim verteilt sich auch auf Bronchialsekrete, und beide passieren die Plazentaschranke und werden in die Muttermilch ausgeschieden.

Geriatrische Pharmakokinetik

Die Pharmakokinetik von Sulfamethoxazol 800 mg und Trimethoprim 160 mg wurde an 6 geriatrischen Probanden (Durchschnittsalter: 78,6 Jahre) und 6 jungen gesunden Probanden (Durchschnittsalter: 29,3 Jahre) unter Verwendung einer nicht von den USA zugelassenen Formulierung untersucht. Die pharmakokinetischen Werte für Sulfamethoxazol bei geriatrischen Probanden waren ähnlich wie bei jungen erwachsenen Probanden. Die mittlere renale Clearance von Trimethoprim war bei geriatrischen Probanden im Vergleich zu jungen erwachsenen Probanden signifikant niedriger (19 ml / h / kg vs. 55 ml / h / kg). Nach der Normalisierung nach Körpergewicht war die scheinbare Gesamtkörperclearance von Trimethoprim bei geriatrischen Probanden im Vergleich zu jungen erwachsenen Probanden um durchschnittlich 19% niedriger.³

Mikrobiologie

Wirkmechanismus

Sulfamethoxazol hemmt die bakterielle Synthese von Dihydrofolsäure durch Konkurrenz mit Para-Aminobenzoesäure (PABA). Trimethoprim blockiert die Produktion von Tetrahydrofolsäure aus Dihydrofolsäure, indem es an das erforderliche Enzym Dihydrofolatreduktase bindet und diese reversibel hemmt. Somit blockiert Doctrim-DS zwei aufeinanderfolgende Schritte bei der Biosynthese von Nukleinsäuren und Proteinen, die für viele Bakterien essentiell sind.

Widerstandsmechanismus

In-vitro-Studien haben gezeigt, dass sich die Bakterienresistenz mit Doctrim-DS langsamer entwickelt als mit Trimethoprim oder Sulfamethoxazol allein.

VERTRETER MINDESTVERHÄNGERUNGSWERTE FÜR ORGANISMEN, DIE FÜR Doctrim-DS (MICμg / ml) geeignet sind

Es wurde gezeigt, dass Doctrim-DS gegen die meisten Stämme der folgenden Mikroorganismen, sowohl in vitro als auch bei klinischen Infektionen, wie in der beschrieben, aktiv ist ANZEIGEN UND VERWENDUNG Sektion.

Aerobe grampositive Mikroorganismen

Streptococcus pneumoniae

Aerobe gramnegative Mikroorganismen

Escherichia coli
Klebsiella Art
Enterobacter Art
Haemophilus influenzae
Morganella Morganii
Proteus mirabilis
Proteus vulgaris
Shigella flexneri
Shigella sonnei

Andere Organismen

Pneumocystis jiroveci

Methoden zur Empfindlichkeitsprüfung

Sofern verfügbar, sollte das klinische Mikrobiologielabor dem Arzt die Ergebnisse von In-vitro-Empfindlichkeitstestergebnissen für antimikrobielle Arzneimittel, die in ansässigen Krankenhäusern verwendet werden, als regelmäßige Berichte zur Verfügung stellen, in denen das Empfindlichkeitsprofil von nosokomialen und in der Gemeinschaft erworbenen Krankheitserregern beschrieben wird. Diese Berichte sollten dem Arzt bei der Auswahl eines antibakteriellen Arzneimittels zur Behandlung helfen.

Verdünnungstechniken

Quantitative Methoden werden verwendet, um antimikrobielle minimale Hemmkonzentrationen (MICs) zu bestimmen. Diese MICs liefern Schätzungen der Anfälligkeit von Bakterien für antimikrobielle Verbindungen. Die MICs sollten unter Verwendung einer standardisierten Testmethode (Brühe oder Agar) bestimmt werden^4,5 Die MIC-Werte sollten gemäß den in Tabelle 1 angegebenen Kriterien interpretiert werden.

Diffusionstechniken

Quantitative Methoden, die eine Messung von Zonendurchmessern erfordern, können auch reproduzierbare Schätzungen der Anfälligkeit von Bakterien für antimikrobielle Verbindungen liefern. Die Zonengröße liefert eine Schätzung der Anfälligkeit von Bakterien für antimikrobielle Verbindungen. Die Zonengröße sollte mit einer standardisierten Testmethode bestimmt werden^5,6 Bei diesem Verfahren werden Papierscheiben verwendet, die mit 1,25 / 23,75 μg Trimethoprim / Sulfamethoxazol imprägniert sind, um die Anfälligkeit von Mikroorganismen für Doctrim-DS zu testen. Die Interpretationskriterien für die Bandscheibendiffusion sind in Tabelle 1 aufgeführt.

Tabelle 1: Interpretationskriterien für Anfälligkeitstests für Trimethoprim / Sulfamethoxazol

Ein Bericht über „anfällig“ zeigt, dass das antimikrobielle Mittel wahrscheinlich das Wachstum des Erregers hemmt, wenn die antimikrobielle Verbindung die Konzentrationen an der Infektionsstelle erreicht, die zur Hemmung des Wachstums des Erregers erforderlich sind. Ein Bericht über „Intermediate“ weist darauf hin, dass das Ergebnis als nicht eindeutig angesehen werden sollte. Wenn der Mikroorganismus nicht vollständig anfällig für alternative, klinisch realisierbare Medikamente ist, sollte der Test wiederholt werden. Diese Kategorie impliziert eine mögliche klinische Anwendbarkeit an Körperstellen, an denen das Arzneimittel physiologisch konzentriert ist, oder in Situationen, in denen eine hohe Dosierung des Arzneimittels angewendet werden kann. Diese Kategorie bietet auch eine Pufferzone, die verhindert, dass kleine unkontrollierte technische Faktoren zu erheblichen Interpretationsunterschieden führen. Ein Bericht über „resistent“ zeigt, dass das antimikrobielle Mittel das Wachstum des Erregers wahrscheinlich nicht hemmt, wenn die antimikrobielle Verbindung die an der Infektionsstelle normalerweise erreichbaren Konzentrationen erreicht. Eine andere Therapie sollte ausgewählt werden.

Qualitätskontrolle

Standardisierte Verfahren zur Empfindlichkeitsprüfung erfordern die Verwendung von Laborkontrollen, um die Genauigkeit und Präzision der im Assay verwendeten Vorräte und Reagenzien sowie die Techniken der Personen, die den Test durchführen, zu überwachen und sicherzustellen^4-6 Standard-Trimethoprim / Sulfamethoxazolpulver sollte den folgenden in Tabelle 2 angegebenen Bereich von MIC-Werten liefern. Für die Diffusionstechnik unter Verwendung der Trimethoprim / Sulfamethoxazol-Scheibe mit 1,25 / 23,75 μg sollten die Kriterien in Tabelle 2 erreicht werden.

Tabelle 2: Akzeptable Qualitätskontrollbereiche für die Empfindlichkeitsprüfung von Trimethoprim / Sulfamethoxazol

REFERENZEN

1. Kremers P., Duvivier J., Heusghem C. Pharmakokinetische Studien zu Co-Trimoxazol beim Menschen nach einmaliger und wiederholter Gabe. J Clin Pharmacol. 1974; 14: 112 & ndash; 117.

2. Kaplan SA, Weinfeld RE, Abruzzen CW, McFaden K, Jack ML, Weissman L. Pharmakokinetisches Profil von Trimethoprimsulfamethoxazol beim Menschen. J Infect Dis. 1973; 128 (Suppl): S547-S555.

3. Varoqaux O et al. Pharmakokinetik der Trimethoprim-Sulfamethoxazol-Kombination bei älteren Menschen. Br J Clin Pharmacol. 1985; 20: 575 & ndash; 581.

4. Institut für klinische und Laborstandards (CLSI). Methoden zur Verdünnung Antimikrobielle Empfindlichkeitstests für Bakterien, die aerob wachsen; Genehmigter Standard - 9. Auflage. CLSI-Dokument M07-A9, Institut für klinische und Laborstandards, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

5. Institut für klinische und Laborstandards (CLSI). Leistungsstandards für Tests zur Empfindlichkeit gegenüber antimikrobiellen Wirkstoffen; Dreiundzwanzigste Ergänzung, CLSI-Dokument M100-S23. CLSI-Dokument M100-S23, Institut für klinische und Laborstandards, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.

6. Institut für klinische und Laborstandards (CLSI). Leistungsstandards für antimikrobielle Festplattendiffusionsempfindlichkeitstests; Genehmigter Standard - CLSI-Dokument M02-A11 der elften Ausgabe, Institut für klinische und Laborstandards, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

Nach oraler Verabreichung werden Trimethoprim und Sulfamethoxazol schnell und nahezu vollständig resorbiert. Das Vorhandensein von Nahrungsmitteln scheint die Absorption nicht zu verzögern. Spitzenwerte im Blut treten zwischen einer und vier Stunden nach der Einnahme auf, und der erreichte Wert hängt mit der Dosis zusammen. Wirksame Werte bleiben bis zu 24 Stunden nach einer therapeutischen Dosis im Blut. Steady-State-Spiegel bei Erwachsenen werden nach 2-3 Tagen Dosierung erreicht. Keine der Komponenten hat einen nennenswerten Einfluss auf die Konzentrationen, die die andere im Blut erreicht.

Trimethoprim ist eine schwache Basis mit einem pKa von 7,4. Es ist lipophil. Die Gewebewerte von Trimethoprim sind im Allgemeinen höher als die entsprechenden Plasmaspiegel, wobei Lunge und Nieren besonders hohe Konzentrationen aufweisen. Die Trimethoprim-Konzentrationen übersteigen die im Plasma bei Galle, Prostataflüssigkeit und Gewebe, Speichel, Sputum und Vaginalsekreten. Die Werte in wässrigem Humor, Muttermilch, Liquor cerebrospinalis, Mittelohrflüssigkeit, Synovialflüssigkeit und Gewebeflüssigkeit (Darm) sind für die antibakterielle Aktivität ausreichend. Trimethoprim gelangt in Fruchtwasser und fetales Gewebe und erreicht Konzentrationen, die denen des mütterlichen Serums entsprechen.

Ungefähr 50% von Trimethoprim im Plasma sind proteingebunden. Die Halbwertszeit beim Menschen liegt bei normaler Nierenfunktion im Bereich von 8,6 bis 17 Stunden. Es wird um den Faktor 1,5 bis 3,0 erhöht, wenn die Kreatinin-Clearance weniger als 10 ml / Minute beträgt. Bei älteren Menschen scheint es keinen signifikanten Unterschied zu jungen Patienten zu geben.

Der Hauptausscheidungsweg für Trimethoprim ist die Niere, und ungefähr 50% der Dosis werden innerhalb von 24 Stunden als unverändertes Arzneimittel im Urin ausgeschieden. Im Urin wurden mehrere Metaboliten identifiziert. Die Harnkonzentrationen von Trimethoprim variieren stark.

Sulfamethoxazol ist eine schwache Säure mit einem pKa von 6,0. Die Konzentration von aktivem Sulfamethoxazol in einer Vielzahl von Körperflüssigkeiten liegt in der Größenordnung von 20 bis 50% der Plasmakonzentration.

Ungefähr 66% von Sulfamethoxazol im Plasma sind proteingebunden und der Hauptausscheidungsweg für Sulfamethoxazol ist die Niere. Die Halbwertszeit beim Menschen beträgt bei normaler Nierenfunktion ungefähr 9 bis 11 Stunden. Es gibt keine Veränderung der Halbwertszeit von aktivem Sulfamethoxazol mit einer Verringerung der Nierenfunktion, aber es gibt eine Verlängerung der Halbwertszeit des Hauptmetaboliten, acetylierter Metaboliten, wenn die Kreatinin-Clearance unter 25 ml / Minute liegt.

Der Hauptausscheidungsweg von Sulfamethoxazol ist die Niere; zwischen 15% und 30% der im Urin zurückgewonnenen Dosis sind in aktiver Form. Bei älteren Patienten ist die renale Clearance von Sulfamethoxazol verringert.