What is responsible for a drug allergy

What is responsible for a drug allergy

Sulfatrim S/S

Generic Name: Sulfonamides and Trimethoprim
This monograph includes information on the following:

1) Sulfadiazine and Trimethoprim*
2) Sulfamethoxazole and Trimethoprim

BAN:
{04}Sulfadiazine—Sulphadiazine
Sulfamethoxazole—Sulphamethoxazole

JAN:
{04}Sulfamethoxazole—Acetylsulfamethoxazole
Sulfamethoxazole—Sulfamethoxazole sodium

VA CLASSIFICATION
Primary: AM650

Commonly used brand name(s): Apo-Sulfatrim2; Apo-Sulfatrim DS2; Bactrim2; Bactrim DS2; Bactrim I.V.2; Bactrim Pediatric2; Cofatrim Forte2; Coptin1; Coptin 11; Cotrim2; Cotrim DS2; Cotrim Pediatric2; Novo-Trimel2; Novo-Trimel D.S.2; Nu-Cotrimox2; Nu-Cotrimox DS2; Roubac2; Septra2; Septra DS2; Septra Grape Suspension2; Septra I.V.2; Septra Suspension2; Sulfatrim2; Sulfatrim Pediatric2; Sulfatrim S/S2; Sulfatrim Suspension2; Sulfatrim-DS2.

Other commonly used names are

• Cotrimazine Sulfadiazine and Trimethoprim

• Cotrimoxazole Sulfamethoxazole and Trimethoprim

• SMZ-TMP Sulfamethoxazole and Trimethoprim
Note:For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Category:

Antibacterial (systemic)—Sulfadiazine and Trimethoprim; *Sulfamethoxazole and Trimethoprim;

Antiprotozoal—Sulfamethoxazole and Trimethoprim;

Indications

Note:Bracketed information in the Indications section refers to uses that are not included in U.S.

product labeling.

General considerations
Sulfonamides, such as sulfadiazine and sulfamethoxazole, used together with trimethoprim, produce synergistic antibacterial activity. {14}{156} Sulfadiazine and sulfamethoxazole own equal antibacterial properties, covering the same spectrum of activity. {14}These sulfonamides, in combination with trimethoprim, are athletic in vitro against numerous gram-positive and gram-negative aerobic organisms.

They own minimal activity against anaerobic bacteria. {104} Susceptible gram-positive organisms include numerous Staphylococcus aureus , including some methicillin-resistant strains, S. saprophyticus , some group A beta-hemolytic streptococci, Streptococcus agalactiae , and most but not every strains of S. pneumoniae . {104} Gram-negative organisms that are susceptible include Escherichia coli, numerous Klebsiella species, Citrobacter diversus and C. fruendii , Enterobacter species, Salmonella species, Shigella species, Haemophilus influenzae , including some ampicillin-resistant strains, H.

ducreyi , Morganella morganii , Proteus vulgaris and P. mirabilis , and some Serratia species. {104} Sulfonamide and trimethoprim combinations also own activity against Acinetobacter species, Pneumocystis carinii, Providencia rettgeri , P. stuarti , Aeromonas , Brucella , and Yersinia species. {104} They are also generally athletic against Neisseria meningitidis , Branhamella (Moraxella) catarrhalis , and some, but not every, N.

gonorrhoeae . {104}Pseudomonas aeruginosa is generally resistant, but P. cepacia and P. maltophilia may be sensitive. {104}

The major difference between sulfadiazine and sulfamethoxazole exists in their respective pharmacokinetics. The primary distinction is that sulfadiazine is metabolized to a much lesser extent than is sulfamethoxazole. {14}{152}{156} This allows for a higher urinary concentration of unchanged sulfadiazine {152}{156}{164}, as well as an increased risk of crystalluria when it is istered in high doses {152}; the antibacterial urinary concentration of sulfadiazine is maintained over a 24-hour interval, allowing for once-a-day dosing in adults.

{150}{164} Also, sulfadiazine achieves higher concentrations in the bile and cerebrospinal fluid. {14}{151}

Accepted

Bronchitis (treatment)—Oral sulfamethoxazole and trimethoprim combination is indicated in adults in the treatment of acute exacerbations of chronic bronchitis caused by susceptible organisms. {03}{05}{18}{22}{38}{168}{170}

Enterocolitis, Shigella species (treatment) —Oral and parenteral sulfamethoxazole and trimethoprim combinations are indicated in the treatment of enterocolitis caused by susceptible strains of Shigella flexneri and S.

sonnei.{01}{03}{05}{21}{38}{168}{169}{170}{171}

Otitis media, acute (treatment)—Oral sulfamethoxazole and trimethoprim combination is indicated in the treatment of acute otitis media caused by susceptible organisms in children. {03}{05}{21}{38}{168}{170}

Pneumonia, Pneumocystis carinii (prophylaxis)1—Oral sulfamethoxazole and trimethoprim combination is indicated in the prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients who are immunocompromised and considered to be at increased risk of developing PCP, including patients with acquired immunodeficiency syndrome (AIDS).

{168}{170} It is considered to be the treatment of choice for this indication. {94} Sulfamethoxazole and trimethoprim combination is indicated in both secondary prophylaxis (patients who own already had at least one episode of PCP), and primary prophylaxis (HIV-infected adults with a CD4 lymphocyte count less than or equal to 200 cells per cubic millimeter and/or less than 20% of entire lymphocytes; every children born to HIV-infected mothers, beginning at 4 to 6 weeks of age, and subsequent prophylaxis given as sure on the basis of age-specific CD4 lymphocyte count{94}) of PCP.

{03}{05}{53}{54}{55}{56}{57}{60}{61}{113}

Pneumonia, Pneumocystis carinii (treatment) —Oral and parenteral sulfamethoxazole and trimethoprim combinations are indicated as primary agents in the treatment of Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). {01}{03}{05}{18}{95}{168}{169}{170}{171}Pentamidine is considered an alternative agent for PCP.

Traveler’s diarrhea (treatment)—Oral sulfamethoxazole and trimethoprim combination is indicated in the treatment of traveler’s diarrhea caused by susceptible strains of enterotoxigenic Escherichia coli and Shigella species.

{03}{18}{38}{138}{139}{168}{170}

Urinary tract infections, bacterial (treatment)— Sulfadiazine and trimethoprim combination {150}{157}{158}{159}{160}{161}{162}{163}{164} and oral and parenteral sulfamethoxazole and trimethoprim combinations {01}{03}{22}{38}{140}{141}{168}{169}{170}{171} are indicated in the treatment of urinary tract infections caused by susceptible organisms.

[Biliary tract infections (treatment)]—Sulfamethoxazole and trimethoprim combination is used in the treatment of biliary tract infections caused by susceptible organisms.

{38}

[Bone and joint infections (treatment)]—Sulfamethoxazole and trimethoprim combination is used in the treatment of bone and joint infections caused by susceptible organisms. {22}{38}

[Chancroid (treatment)]1—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of chancroid. {38}{147}{148}{149}

[Chlamydial infections (treatment) ]1—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of chlamydial infections.

{37}

[Cyclospora infections (treatment) ]1—Sulfamethoxazole and trimethoprim combination is used in the treatment of diarrhea caused by Cyclospora cayetanensis , but may not completely eradicate the organism. {106}{107}{108}{109}

[Endocarditis, bacterial (treatment) ]1—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of bacterial endocarditis caused by susceptible organisms.

{37}{38}

[Gonorrhea, endocervical and urethral, uncomplicated (treatment)]—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of gonorrhea caused by susceptible organisms. {22}{38}{146}

[Granuloma inguinale (treatment)]1—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of granuloma inguinale.

{37}{145}

[HIV-related infections in Africa (prophylaxis)]1—Sulfamethoxazole and trimethoprim combination is used in the prophylaxis of HIV-related infections in Africa{172}{173}{174}.
—Given the large number of patients with HIV-related infections throughout Africa and the high mortality they experience, sulfamethoxazole and trimethoprim combination prophylaxis if widely applicable and implemented could significantly affect care and survival (i.e., could significantly lower morbidity and mortality) among HIV-infected patients in Africa{172}{173}{174}.

[Isosporiasis (prophylaxis and treatment) ]1—Sulfamethoxazole and trimethoprim combination is used in the prophylaxis and treatment of isosporiasis caused by Isospora belli .

{38}{39}{40}{104}

[Lymphogranuloma venereum (treatment) ]1—Sulfamethoxazole and trimethoprim combination is used in the treatment of lymphogranuloma venereum. {38}{104}

[Meningitis (treatment)]—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of meningitis caused by susceptible organisms. {37}{38}

[Nocardiosis (treatment)]—Sulfamethoxazole and trimethoprim combination is used in the treatment of nocardiosis.

{22}{38}{104}{137}

[Paracoccidioidomycosis (treatment) ]1—Sulfamethoxazole and trimethoprim combination is used in the treatment of paracoccidioidomycosis. {38}

[Paratyphoid fever (treatment)] or
[Typhoid fever (treatment)]—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of paratyphoid and typhoid fevers caused by susceptible strains.

{22}{38}

[Septicemia, bacterial (treatment)]—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of bacterial septicemia caused by susceptible organisms. {37}{38}

[Sinusitis (treatment)]1—Sulfamethoxazole and trimethoprim combination is used in the treatment of sinusitis caused by susceptible organisms. {38}{103}{104}

[Skin and soft tissue infections (treatment)]—Sulfamethoxazole and trimethoprim combination is used in the treatment of skin and soft tissue infections, including burn wound infections caused by susceptible organisms.

{22}

[Toxoplasmosis (prophylaxis)]1—Sulfamethoxazole and trimethoprim combination is used in the primary prophylaxis of toxoplasmosis in patients with AIDS. {38}{94}{95}{100}{114}{115}{167}

[Urinary tract infections, bacterial (prophylaxis)]1—Sulfamethoxazole and trimethoprim combination is used in the prophylaxis of bacterial urinary tract infections. {37}{102}{142}

[Whipple’s disease (treatment)]1—Sulfamethoxazole and trimethoprim combination is used in the treatment of Whipple’s disease.

{104}{105}{109}{110}{111}{112}

—Not every strains of a specific organism may be susceptible to sulfonamide and trimethoprim combinations.

Unaccepted
Sulfamethoxazole and trimethoprim combination is not indicated for prophylaxis or prolonged therapy in otitis media. {03}{168}{170} Sulfamethoxazole and trimethoprim combination is not effective in the treatment of syphilis{37}{38} andUreaplasm urealyticum{37}.

Sulfamethoxazole and trimethoprim combination should not be used in the treatment of group A beta-hemolytic streptococcal tonsillopharyngitis since it may not eradicate streptococci and therefore may not prevent sequelae such as rheumatic fever.

{01}{05}{37}

1Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
Sulfadiazine: 250.28 {04}
Sulfamethoxazole: 253.28 {04}
Trimethoprim: 290.32 {04}

Mechanism of action/Effect:

Sulfonamides:

Sulfonamides are broad-spectrum, bacteriostatic anti-infectives.

{22} They are structural analogs of para-aminobenzoic acid (PABA) and competitively inhibit a bacterial enzyme, dihydropteroate synthetase, that is responsible for incorporation of PABA into dihydrofolic acid, the immediate precursor of folic acid. {23} This blocks the synthesis of dihydrofolic acid and decreases the quantity of metabolically athletic tetrahydrofolic acid, a cofactor for the synthesis of purines, thymidine, and DNA. {37}

Susceptible bacteria are those that must synthesize folic acid. Mammalian cells require preformed folic acid and cannot synthesize it.

{37}{38} The action of sulfonamides is antagonized by PABA and its derivatives (e.g., procaine and tetracaine) and by the presence of pus or tissue breakdown products, which provide the necessary components for bacterial growth. {23}

Trimethoprim:

Trimethoprim is a bacteriostatic lipophilic feeble base structurally related to pyrimethamine. It binds to and reversibly inhibits the bacterial enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. {03}{22}{37} This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with bacterial nucleic acid and protein production.

{23} Bacterial dihydrofolate reductase is approximately 50,000 to 100,000 times more tightly bound by trimethoprim than is the corresponding mammalian enzyme. {37}{38}

Trimethoprim exerts its effect at a step in the folate biosynthesis immediately subsequent to the one at which sulfonamides exert their effect. When trimethoprim is istered concurrently with sulfonamides, synergism occurs, which is attributed to inhibition of tetrahydrofolate production at 2 sequential steps in its biosynthesis.

{22}{23}{37}

Absorption:

Oral—Sulfonamides and trimethoprim are rapidly and well absorbed (70 to 100%). {22}{151}{152}

Distribution:

Sulfonamides:

Widely distributed throughout body tissues and fluids, including pleural {01}{23}{165}, peritoneal {01}{23}{165}, synovial {01}{23}{165}, middle ear {01}{23}, and ocular fluids {01}{23}{165}, as well as nasal secretions {154}, sputum {01}{23}, and prostate {152}, lymph {153}, and renal tissue {152}.

Sulfadiazine is distributed throughout entire body water {23}{37} and achieves higher concentrations in bile than does sulfamethoxazole {14}. Sulfonamides readily cross the placenta and are distributed into breast milk, also. {01}{23}{37} Sulfonamides penetrate into the cerebrospinal fluid (CSF) with CSF concentrations of sulfadiazine reaching 32 to 65% {151} and those of sulfamethoxazole reaching 14 to 30% of the corresponding blood concentrations. {23}{27}{37}{38} Sulfonamides may be detected in the urine in approximately 30 minutes. {23}

Trimethoprim:

Rapidly and widely distributed to various tissues and fluids, including kidneys, liver, spleen, bronchial secretions, saliva, sputum, middle ear, and prostatic tissue and fluid.

{01}{23}{37} Trimethoprim is also distributed into bile, aqueous humor, bone, mucosa, and seminal fluid. {37}{38} It penetrates into the CSF with CSF concentrations reaching 20 to 40% of corresponding plasma concentrations. {37}{38} Trimethoprim crosses the placenta and is distributed into breast milk. {01}{37}

Urine solubility:

Sulfadiazine: Acetylated sulfadiazine has the least solubility, followed by sulfadiazine.

{152}

Sulfamethoxazole: Acetylated sulfamethoxazole is more soluble than sulfadiazine, but less soluble than sulfamethoxazole. {152}

Vol D:

Sulfadiazine: Approximately 33.7 liters. {165}

Sulfamethoxazole: Approximately 0.21 liters per kg of body weight (L/kg). {23}{37}

Trimethoprim: Approximately 1.8 L/kg. {23}{37}

Protein binding:

Sulfonamides:

Sulfonamides compete with bilirubin for binding to albumin.

Kernicterus may develop in premature infants or neonates. {37} Binding is decreased in patients with severely impaired renal function. {38} Only free, unbound drug has antibacterial activity. {27}

Sulfadiazine: Moderate (38 to 56%). {151}{152}

Sulfamethoxazole: Moderate to high (60 to 70%). {01}{23}{38}

Trimethoprim:

Moderate (40 to 45%). {01}{23}{24}{37} Protein binding does not significantly decrease in patients with uremia. {38}

Biotransformation:

Sulfonamides—Hepatic; primarily by acetylation to inactive metabolites, which retain the toxicity of the parent compound.

{23} Some hepatic glucuronide conjugation may happen. {37}

Trimethoprim—Hepatic; 10 to 20% metabolized to inactive metabolites by O-demethylation, ring N-oxidation, and alpha-hydroxylation; metabolites may be free or conjugated. {24}

Half-life:

Sulfadiazine:

Normal renal function: 9 to 13.7 hours.

What is responsible for a drug allergy

{152}{155}{156}

Renal failure: Approximately 34 hours. {23}{38}

Sulfamethoxazole:

Normal renal function: 10 to 12 hours. {01}{03}{22}{23}{37}{38}

Creatinine clearance less than 10 mL per minute (mL/min) (0.17 mL per second [mL/sec]): 18 to 50 hours. {38}{118}

Trimethoprim:

Normal renal function: 8 to 10 hours.

{01}{03}{22}{23}{24}{37}{152}{156}

Creatinine clearance less than 10 mL/min (0.17 mL/sec): Approximately 24 hours. {38}{118}

Time to peak serum concentration

Oral:

Sulfadiazine: 2.7 to 4 hours. {152}{155}{156}

Sulfamethoxazole: 2 to 4 hours. {22}{23}

Trimethoprim: 1 to 4 hours. {03}{22}{23}{37}{38}{156}

Peak serum concentration:

Sulfadiazine:

Single 820-mg dose: 27.5 to 31.7 mcg/mL.

{152}{155}{156}

Sulfamethoxazole:

Oral, 800 mg twice a day: Approximately 40 mcg/mL. {23}{38}

Intravenous, 800 mg three times a day: Approximately 106 mcg/mL. {37}{38}

Trimethoprim:

Oral, 160 mg twice a day: Approximately 2 to 2.4 mcg/mL. {23}{38}{156}

Intravenous, 160 mg three times a day: Approximately 9 mcg/mL. {37}{38}

Elimination:

Sulfonamides—
Renal, by glomerular filtration, with some tubular secretion {01} and reabsorption of both athletic medication and metabolites.

Excretion is increased in alkaline urine {37}{38}.

Percent of medication unchanged in the urine—
Sulfadiazine: 43 to 58% in 24 hours. {151}{155}{156}
Sulfamethoxazole: 20 to 40%. {23}{37}

Little amounts are excreted in the feces, bile, and other body secretions. {38}

In dialysis—
Sulfamethoxazole is removed from the blood by hemodialysis.

{21}{37} However, peritoneal dialysis is not effective. {27}{118}

Trimethoprim—
Renal, 40 to 60% excreted within 24 hours, primarily by glomerular filtration and tubular secretion {03}{22}{23}{37}{156}; of this quantity, 80 to 90% is excreted unchanged and the remainder is excreted as inactive metabolites.

{37} Excretion is increased in acid urine and decreased in alkaline urine. {38}
Little amounts are excreted in the feces and bile. {22}

In dialysis—
Significant amounts of trimethoprim are removed from the blood by hemodialysis {21}, requiring a full maintenance dose after dialysis. Peritoneal dialysis is not effective in removing trimethoprim from the blood. {118}

Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to sulfonamides or trimethoprim may be allergic to sulfonamide and trimethoprim combinations.

{01}{150}

Patients allergic to furosemide, thiazide diuretics, sulfonylureas, or carbonic anhydrase inhibitors may be allergic to sulfonamides also. {25}{26}

Patients sensitive to sulfites may own an allergic reaction to Bactrim I.V. since it contains sodium metabisulfite. {01}

Carcinogenicity

Sulfamethoxazole and trimethoprim—Long-term studies to assess the carcinogenic potential of sulfamethoxazole and trimethoprim combination own not been done. {01}

Mutagenicity

Sulfamethoxazole and trimethoprim—Bacterial mutagenicity studies with sulfamethoxazole and trimethoprim combination own not been done.

Trimethoprim has not been shown to be mutagenic in the Ames assay. Studies in human leukocytes cultured in vitro with sulfamethoxazole and trimethoprim combination, using concentrations that exceeded therapeutic serum concentrations, own not shown that sulfamethoxazole and trimethoprim combination causes chromosomal damage. {01}

Pregnancy/Reproduction
Fertility—
Sulfamethoxazole and trimethoprim: Studies in rats, given oral doses as high as 70 mg of trimethoprim per kg of body weight (mg/kg) and 350 mg/kg of sulfamethoxazole daily, own not shown that sulfamethoxazole or trimethoprim causes any adverse effects on fertility or general reproductive performance.

{01}

Pregnancy—
Sulfadiazine: FDA Pregnancy Category C. {151}

Sulfamethoxazole and trimethoprim: Sulfamethoxazole and trimethoprim cross the placenta. Adequate and well-controlled studies in humans own not been done. {01} However, prophylaxis for Pneumocystis carinii pneumonia (PCP) is recommended in HIV-infected pregnant women. {94} In one retrospective study in 186 women who received placebo or sulfamethoxazole and trimethoprim combination during pregnancy, the incidence of congenital abnormalities was lower (3.3% versus 4.5%) in the sulfamethoxazole and trimethoprim combination–treated group.

No abnormalities were reported in the 10 children whose mothers received sulfamethoxazole and trimethoprim combination during the first trimester. In another study, no congenital abnormalities were reported in 35 children whose mothers received sulfamethoxazole and trimethoprim combination at the time of conception or shortly thereafter. However, sulfamethoxazole and trimethoprim may interfere with folic acid metabolism in the fetus. {01}

Studies in rats given oral doses of 200 mg/kg of trimethoprim and 533 mg/kg of sulfamethoxazole own shown that sulfamethoxazole causes teratogenic effects (primarily cleft palates).

However, doses of 192 mg/kg of trimethoprim and 512 mg/kg of sulfamethoxazole, when istered separately, did not cause cleft palates in rats. Doses of 88 mg/kg of trimethoprim and 355 mg/kg of sulfamethoxazole own been shown to cause cleft palates when istered concurrently. {01} Studies in rabbits given doses of trimethoprim 6 times the usual human therapeutic dose own shown that trimethoprim causes an increase in the number of dead, resorbed, and malformed fetuses. {01}

FDA Pregnancy Category C. {01}

Labor and delivery—

Sulfonamides are not recommended at term since they may cause jaundice, hemolytic anemia, and kernicterus in the newborn.

{26}{38}

Breast-feeding

Sulfonamides—Sulfonamides are distributed into breast milk. {01} Use is not recommended in nursing women since sulfonamides may cause kernicterus in nursing infants. {01}{18}{150} Also, sulfonamides may cause hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD)–deficient infants. {26}

Trimethoprim—Trimethoprim is distributed into breast milk. {01} Trimethoprim may interfere with folic acid metabolism in nursing infants.

Pediatrics

Sulfonamides compete for bilirubin binding sites on plasma albumin, increasing the risk of kernicterus in the newborn.

Also, because the acetyltransferase system is not fully developed in the newborn, increased blood concentrations of the free sulfonamide can further increase the risk of kernicterus. {26}{38}

Sulfadiazine and trimethoprim:

Sulfadiazine and trimethoprim combination is not recommended in premature infants and neonates up to 12 weeks of age. {150}

Sulfamethoxazole and trimethoprim:

Although sulfamethoxazole and trimethoprim combination is indicated in the treatment of acute otitis media in children, it is not indicated for prophylaxis or prolonged therapy.

{03}

Except as concurrent adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis or for the prophylaxis of Pneumocystis carinii pneumonia (PCP) in infants 4 weeks of age or over, the use of sulfamethoxazole and trimethoprim combination is contraindicated in infants up to 2 months of age since sulfonamides may cause kernicterus in neonates. {18}{56}

Geriatrics

Elderly patients may be at increased risk of severe side/adverse effects.

Severe skin reactions, generalized bone marrow depression, and decreased platelet count (with or without purpura) are the most frequently reported severe side/adverse effects in the elderly. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients who are receiving diuretics, primarily thiazides, concurrently with sulfonamide and trimethoprim combinations. {01}{18}{27}{150}

Pharmacogenetics
Sulfonamides are metabolized primarily by acetylation.

{41} Patients can be divided into 2 groups, slow and quick acetylators. Slow acetylators own a higher incidence of severe sulfonamide reactions, although a slow acetylator phenotype is not thought to be the sole reason for sulfonamide toxicity. {41}{42}{43}{44}{83} The incidence of the slow acetylator phenotype is approximately 50% in North American blacks and whites. {41}{42}{45}{83} Approximately 30% of the Hispanic population {43} and 10% of the Asian population {42} are slow acetylators.

Also, acquired immunodeficiency syndrome (AIDS) patients with acute illness, but not AIDS patients who are stable or human immunodeficiency virus (HIV)-infected patients without AIDS, own an increased incidence of slow acetylation. {43}

Dental

The leukopenic and thrombocytopenic effects of sulfonamides may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding.

If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts own returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems own been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (»=major clinical significance):

Note:Combinations containing any of the following medications, depending on the quantity present, may also interact with this medication.

» Anticoagulants, coumarin- or indandione-derivative or {01}{47}{124}{125}{150}{168}{169}{170}{171}
» Anticonvulsants, hydantoin or {01}{47}{122}{150}{168}{169}{170}{171}
» Antidiabetic agents, oral {47}{120}{121}{150}{168}{170}{171}(these medications may be displaced from protein binding sites and/or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy)

Atovaquone {149}(concurrent istration of sulfamethoxazole and trimethoprim combination with atovaquone suspension resulted in an 8 and 17% decrease in the steady-state serum concentration of sulfamethoxazole and trimethoprim, respectively; this effect is thought to be minor and is not expected to produce clinically significant events)

Bone marrow depressants (See Appendix II )(concurrent use of bone marrow depressants with sulfonamides may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, shut observation for myelotoxic effects should be considered)

Contraceptives, estrogen-containing, oral {29}(concurrent long-term use of sulfonamides may result in reduced contraceptive reliability and increased incidence of breakthrough bleeding)

Cyclosporine {47}{48}{49}{50}{168}(concurrent use with sulfonamides may increase the metabolism of cyclosporine, resulting in decreased plasma concentrations and potential transplant rejection; there may also be additive nephrotoxicity; plasma cyclosporine concentrations and renal function should be monitored)

Dapsone {35}(concurrent use with trimethoprim will generally increase the plasma concentrations of both dapsone and trimethoprim, possibly due to an inhibition in dapsone metabolism, and/or competition for renal secretion between the 2 medications; increased serum dapsone concentrations may increase the number and severity of side effects, especially methemoglobinemia)

» Digoxin {168}(concurrent use with trimethoprim and sulfamethoxazole may increase the serum concentration of digoxin; serum digoxin levels should be monitored)

Folate antagonists, other (See Appendix II ) {150}(concurrent use with trimethoprim or use of trimethoprim between courses of other folic acid antagonists is not recommended because of the possibility of megaloblastic anemia)

» Hemolytics, other (See Appendix II )(concurrent use with sulfonamides may increase the potential for toxic side effects)

» Hepatotoxic medications, other (See Appendix II )(concurrent use with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged istration or those with a history of liver disease, should be carefully monitored)

Lamivudine (3TC)(in one little study, sulfamethoxazole and trimethoprim combination was found to decrease significantly the clearance, steady-state volume of distribution, and elimination half-life of lamivudine {36}; trimethoprim was also found to decrease the renal clearance of lamivudine by approximately 59% in an isolated perfused rat kidney {67})

» Methenamine {37}{38}(in acid urine, methenamine breaks below into formaldehyde, which may form an insoluble precipitate with certain sulfonamides and may also increase the harm of crystalluria; concurrent use is not recommended)

» Methotrexate or {01}{38}{51}{123}{150}{168}{169}{170}{171}
Phenylbutazone or {37}{38}{150}
Sulfinpyrazone {18}{38}{150}(the effect of methotrexate may be potentiated during concurrent use with sulfonamides because of displacement from plasma protein binding sites; phenylbutazone and sulfinpyrazone may displace sulfonamides from plasma protein-binding sites, increasing sulfonamide concentrations)

Procainamide {31}{32}(concurrent use with trimethoprim may increase the plasma concentration of both procainamide and its metabolite, N-acetylprocainamide [NAPA], by decreasing their renal clearance)

Rifampin {30}{38}(concurrent use may significantly increase the elimination and shorten the elimination half-life of trimethoprim)

Thiazide diuretics {01}(there has been an increased incidence of thrombocytopenia with purpura in elderly patients who received sulfamethoxazole and trimethoprim combination with thiazide diuretics)

Tricyclic antidepressants(efficacy of tricyclic antidepressants may be decreased)

Laboratory worth alterations
The following own been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (»=major clinical significance):

With diagnostic test results
Benedict»s test {37}{52}(sulfonamides may produce a false-positive Benedict»s test for urine glucose )

Creatinine determinations {01}{18}{168}(trimethoprim may interfere with the Jaffé alkaline picrate assay for creatinine, resulting in creatinine values that are approximately 10% higher than actual values)

Methotrexate assays, serum {01}{18}{168}{169}(trimethoprim may interfere with serum methotrexate assays if methotrexate is measured by the competitive binding protein technique [CBPA] using a bacterial dihydrofolate reductase as the binding protein; no interference occurs if methotrexate is measured by radioimmunoassay [RIA])

Sulfosalicylic acid test {37}{52}(sulfonamides may produce a false-positive sulfosalicylic acid test for urine protein)

Urine urobilinogen test strip (e.g., Urobilistix) {37}{52}(sulfonamides may interfere with the Urobilistix test for urinary urobilinogen )

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin, serum(concentrations may be increased {01}{18}{66}{150})

Blood urea nitrogen (BUN) and
Creatinine, serum(concentrations may be increased {01}{37}{49}{66})

Glucose, blood(concentrations may be decreased, resulting in hypoglycemia on rare occasions {65})

Potassium, serum(concentrations may be increased; this generally occurs with higher doses, such as for the treatment of Pneumocystis carinii pneumonia, but may also happen at regular doses {76}{77}{78}{79}{80}{81})

Medical considerations/Contraindications
The medical considerations/contraindications included own been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (»=major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problem exists:
» Allergy to sulfonamides, furosemide, thiazide diuretics, sulfonylureas, carbonic anhydrase inhibitors, sulfites, or trimethoprim {01}{18}
Risk-benefit should be considered when the following medical problems exist
» Blood dyscrasias or
» Megaloblastic anemia due to folate deficiency {01}{24}{27}{168}{169}{170}{171}(trimethoprim may cause folic acid deficiency; sulfonamides and trimethoprim may cause blood dyscrasias)

» Glucose-6-phosphate dehydrogenase (G6PD) deficiency {01}{37}{116}{117}{150}{168}{169}{170}{171}(hemolysis may rarely occur; frequency may be dose-related)

» Hepatic function impairment {01}{21}{150}{168}{169}{170}{171}(sulfonamides and trimethoprim are metabolized in the liver; delayed metabolism may increase the risk of toxicity; also, sulfonamides may cause fulminant hepatic necrosis)

» Porphyria {26}{28}(sulfonamides may precipitate an acute attack of porphyria)

» Renal function impairment {01}{21}{27}{150}{168}{169}{170}{171}(sulfonamides and trimethoprim are renally excreted; delayed elimination may increase the risk of toxicity; sulfonamides may cause tubular necrosis or interstitial nephritis)

Patient monitoring
The following may be especially significant in patient monitoring (other tests may be warranted in some patients, depending on condition; »=major clinical significance):

Finish blood counts (CBCs) {01}{27}{150}{168}{169}{170}{171}(may be required prior to and monthly during treatment to detect blood dyscrasias in patients on prolonged therapy; therapy should be discontinued if a significant decrease in the count of any formed blood elements occurs)

Urinalyses {01}{27}{150}{168}{169}{170}{171}(may be required prior to and periodically during treatment to detect crystalluria and/or urinary calculi formation in patients on long-term or high-dose therapy and in patients with impaired renal function)

Side/Adverse Effects

Note:Fatalities own occurred, although rarely, due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.

Therapy should be discontinued at the first appearance of skin rash or any serious side/adverse effects or if signs of folic acid deficiency happen. {01}{18}{168}{169}{170}{171}
Patients infected with human immunodeficiency virus (HIV) own a greater incidence of side/adverse effects, especially rash, fever, and leukopenia, than do non-HIV–infected patients. {01}{85}{86}{168}{169}{170}{171} On rare occasions, adverse reactions may become extremely severe or life-threatening. {85}{86}{87}{88} Adverse effects may happen in up to 65% of acquired immunodeficiency syndrome (AIDS) patients {66}{84}, with 24 to 57% having such severe toxicity that therapy has to be discontinued.

{66} Sulfamethoxazole and trimethoprim combination desensitization in HIV-infected patients has been successful in some patients, who own then been capable to tolerate regular dosing for the prophylaxis of Pneumocystis carinii pneumonia (see Selected Bibliography). {89}{90}{91}{92}{93}{166}
The multiorgan toxicity of sulfonamides is thought to be the result of the way sulfonamides are metabolized in certain patients. It is probably due to the inability of the body to detoxify reactive metabolites.

Sulfonamides are metabolized primarily by acetylation. {41}{83}{135} Patients can be divided into slow and quick acetylators. Slow acetylation of sulfonamides makes more of the medication available for metabolism by the oxidative pathways of the cytochrome P-450 system. {44}{45}{83} These pathways produce reactive toxic metabolites, such as hydroxylamine and nitroso compounds. {43}{44}{45}{135} The metabolites are normally detoxified by scavengers, such as glutathione. However, some populations, such as HIV-infected patients, own low concentrations of glutathione and these metabolites accumulate, producing toxicity.

{43}{46}{83}{135} Patients who are slow acetylators own a higher incidence of sulfonamide hypersensitivity reactions {41}{42}{43}{44}, although severe toxicity has also been seen in quick acetylators. {41} Acetylation status alone cannot fully explain sulfonamide toxicity {45}{83} since approximately 50% of North American blacks and whites are slow acetylators and severe reactions happen in less than 1% of patients treated with sulfonamides.

{45} However, decreased acetylation may increase the quantity of sulfonamide metabolized to toxic metabolites. {45}{135}
Sulfonamides own been associated with crystalluria in the past; however, the risk is little with current sulfonamides and the doses used. Acetylated sulfadiazine has the least solubility, followed by sulfadiazine, acetylated sulfamethoxazole, and sulfamethoxazole. {152} Solubility also varies with pH and dose. The risk of crystalluria is high with sulfadiazine at a combined dose of 6 grams a day (4920 mg of sulfadiazine and 1080 mg of trimethoprim); however, this is 6 times the recommended daily dose.

{152}

The following side/adverse effects own been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Hypersensitivity (fever; itching; skin rash){01}{18}{37}{66}

photosensitivity (increased sensitivity of skin to sunlight){01}{18}{37}

Incidence less frequent

Blood dyscrasias (fever and sore throat; pale skin; unusual bleeding or bruising; unusual tiredness or weakness){01}{18}{23}{59}{66}{133}{134}{150}{168}{169}{170}{171}

cholestatic hepatitis (yellow eyes or skin ){01}{68}{69}{70}{71}{129}{130}{150}{168}{169}{170}{171}

pancreatitis (back or stomach pain, severe; quick heart beat; fever; nausea or vomiting; swelling of the stomach){168}{169}{170}{171}

Stevens-Johnson syndrome (aching joints and muscles; redness, blistering, peeling, or loosening of skin; unusual tiredness or weakness){01}{18}{23}{37}{150}{168}{169}{170}{171}

toxic epidermal necrolysis ( difficulty in swallowing; redness, blistering, peeling, or loosening of skin){01}{18}{23}{37}{150}{168}{169}{170}{171}

Incidence rare

Aseptic meningitis (confusion; drowsiness; general feeling of illness; severe headache; nausea; stiff neck and/or back){01}{33}{34}{72}{73}{74}{75}{131}{132}{168}{169}{170}{171}

central nervous system (CNS) toxicity (anxiety; hallucinations; mental depression; nervousness; seizures (convulsions)){01}{126}{127}{128}{150}{168}{169}{170}{171}

Clostridium difficile colitis ( severe abdominal or stomach cramps and pain; abdominal tenderness ; watery and severe diarrhea, which may also be bloody; fever)—may happen up to several weeks after discontinuation of medication{01}{82}{136}

crystalluria or hematuria (blood in urine ; lower back pain; pain or burning while urinating){01}{152}

goiter or thyroid function disturbance ( swelling of front part of neck){01}{37}

interstitial nephritis or tubular necrosis (greatly increased or decreased frequency of urination or quantity of urine; increased thirst; loss of appetite ; nausea; vomiting){01}{37}{150}{168}{169}{170}{171}

methemoglobinemia (bluish fingernails, lips, or skin; hard breathing; pale skin; sore throat and fever; unusual bleeding or bruising; unusual tiredness or weakness){01}{37}{168}{169}{170}{171}

rhabdomyolysis ( fatigue; muscle pain; muscle weakness)—has been reported mainly in AIDS patients

thrombophlebitis (pain at site of injection){01}{37}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

CNS effects (dizziness; headache; ringing in the ears; tiredness){01}{23}{37}{150}

gastrointestinal disturbances (abdominal pain ; diarrhea; loss of appetite; nausea or vomiting){01}{18}{23}{37}{66}{150}

glossitis or stomatitis (mouth sores; swelling of the tongue){168}{169}{170}{171}

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sulfonamides and Trimethoprim (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
» Conditions affecting use, especially:
Allergy to sulfonamides, furosemide, thiazide diuretics, sulfonylureas, carbonic anhydrase inhibitors, sulfites, or trimethoprim

Pregnancy—Sulfonamides and trimethoprim cross the placenta; trimethoprim may interfere with folic acid metabolism; use is not recommended at term since sulfonamides may cause jaundice, hemolytic anemia, and kernicterus in neonates

Breast-feeding—Sulfonamides and trimethoprim are distributed into breast milk; sulfonamides may cause kernicterus in nursing infants; trimethoprim may interfere with folic acid metabolism

Use in children—Sulfadiazine and trimethoprim combination is contraindicated in infants up to 3 months of age and sulfamethoxazole and trimethoprim combination is contraindicated in infants up to 2 months of age for most indications since sulfonamides may cause kernicterus in neonates; however, sulfamethoxazole and trimethoprim combination is indicated in every infants born to human immunodeficiency virus (HIV)–infected mothers, starting at 4 to 6 weeks

Use in the elderly—Elderly patients, especially those also taking diuretics, may be at increased risk of severe side/adverse effects
Other medications, especially coumarin- or indandione-derivative anticoagulants, hydantoin anticonvulsants, oral antidiabetic agents, other hemolytics, other hepatotoxic medications, methenamine, or methotrexate
Other medical problems, especially blood dyscrasias, G6PD deficiency, hepatic function impairment, megaloblastic anemia due to folic acid deficiency, porphyria, and renal function impairment

Proper use of this medication
» Not giving sulfadiazine and trimethoprim combination to infants under 3 months of age, or sulfamethoxazole and trimethoprim combination to infants under 2 months of age, except under special circumstances

» Maintaining adequate fluid intake

Proper istration technique for oral liquids

» Compliance with full course of therapy

» Importance of not missing doses and taking at evenly spaced times

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check blood counts

Checking with physician if no improvement within a few days

Caution in use of regular toothbrushes, dental floss, and toothpicks; deferring dental work until blood counts own returned to normal; checking with physician or dentist concerning proper oral hygiene

» Possible skin photosensitivity

» Caution if dizziness occurs

Side/adverse effects
Severe skin problems and blood problems may be more likely to happen in elderly patients who are taking sulfamethoxazole and trimethoprim combination, especially if diuretics are being taken concurrently

Signs of potential side effects, especially hypersensitivity, photosensitivity, blood dyscrasias, cholestatic hepatitis, pancreatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, aseptic meningitis, central nervous system toxicity, Clostridium difficile colitis, crystalluria, hematuria, goiter, thyroid function disturbance, interstitial nephritis, tubular necrosis, methemoglobinemia, rhabdomyolysis and thrombophlebitis

General Dosing Information
Fluid intake should be sufficient to maintain urine output of at least 1200 mL per day in adults.

{05}{18}

Adults with renal function impairment require a reduction in dose in sulfonamide and trimethoprim combinations as follows: {01}{150}

SULFADIAZINE AND TRIMETHOPRIM

Summary of Differences
Indications: Sulfadiazine and trimethoprim combination is recommended for use only in the treatment of urinary tract infections.

Pharmacology/pharmacokinetics: Compared to sulfamethoxazole, sulfadiazine achieves higher concentrations in the bile and cerebrospinal fluid, is metabolized to a lesser extent, and a higher percentage of athletic medication is eliminated in the urine.

{14}{23}{37}{151}{152}{155}{156}{165}

Additional Dosing Information
The usual length of therapy when treating an uncomplicated lower urinary tract infection with sulfadiazine and trimethoprim combination is three {157}{159}{160} to five {158} days in women and seven to ten days in men {64}. Therapy should be continued for fourteen days or more in upper urinary tract infections.

{64}

Oral Dosage Forms

SULFADIAZINE AND TRIMETHOPRIM ORAL SUSPENSION

Usual adult and adolescent dose
Antibacterial
Oral, 820 mg of sulfadiazine and 180 mg of trimethoprim once a day. {150}

Usual pediatric dose
Antibacterial
Infants up to 3 months of age: Use is not recommended. {150}

Children 3 months to 12 years of age: Oral, 7 mg of sulfadiazine and 1.5 mg of trimethoprim per kg of body weight every twelve hours. {150}

Children over 12 years of age: See Usual adult and adolescent dose.{150}

Strength(s) generally available
U.S.—
Not commercially available.

Canada—

205 mg of sulfadiazine and 45 mg of trimethoprim per 5 mL (Rx) [Coptin]

Packaging and storage:
Store under 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
• Shake well.
• Take with a full glass of water.
• May cause dizziness.
• Avoid too much sun or use of sunlamp.
• Continue medicine for full time of treatment.

Note:When dispensing, include a calibrated liquid-measuring device.

SULFADIAZINE AND TRIMETHOPRIM TABLETS

Usual adult and adolescent dose
See Sulfadiazine and Trimethoprim Oral Suspension .

{150}

Usual pediatric dose
See Sulfadiazine and Trimethoprim Oral Suspension . {150}

Strength(s) generally available
U.S.—
Not commercially available.

Canada—

410 mg of sulfadiazine and 90 mg of trimethoprim (Rx) [Coptin]

820 mg of sulfadiazine and 180 mg of trimethoprim (Rx) [Coptin 1]

Packaging and storage:
Store under 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
• Take with a full glass of water.
• May cause dizziness.
• Avoid too much sun or use of sunlamp.
• Continue medicine for full time of treatment.

SULFAMETHOXAZOLE AND TRIMETHOPRIM

Summary of Differences
Pharmacology/pharmacokinetics: Sulfamethoxazole is more soluble in urine than is sulfadiazine.

{152}

Additional Dosing Information
Therapy should be continued for at least ten to fourteen days in acute exacerbations of chronic bronchitis {05}; as single-dose therapy or for three to five {119} days in urinary tract infections {101}{140}{141}{143}{144}; for five {05} to seven {119} days in shigellosis; for ten days in acute otitis media in children {05}; for five days in travelers diarrhea {05}; and for fourteen to twenty-one days in Pneumocystis carinii pneumonia {05}.

Sulfamethoxazole and trimethoprim combination may also be given for one or two days or as single-dose therapy for lower urinary tract infections. Therapy should be continued for fourteen days or more in upper urinary tract infections. {64}

Oral Dosage Forms

Note:Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

SULFAMETHOXAZOLE AND TRIMETHOPRIM ORAL SUSPENSION USP

Usual adult and adolescent dose
Antibacterial (systemic)
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim every twelve hours.

{03}{05}

Antiprotozoal

Pneumocystis carinii pneumonia {03}:

Treatment—
Oral, 18.75 to 25 mg of sulfamethoxazole and 3.75 to 5 mg of trimethoprim per kg of body weight every six hours for fourteen to twenty-one days {03}{05}{168}{169}{170}{171}.

Prophylaxis1
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim once a day. {05}{94}{97}{98}{99}{168}{170}

Acceptable alternative dosing schedules include—
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim three times a week (e.g., Monday, Wednesday, Friday) {55}{62}{63}{94}.

Oral, 400 mg of sulfamethoxazole and 80 mg of trimethoprim once a day {94}{96}{99}.

[Toxoplasmosis (prophylaxis)]1:
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim once a day.

{94}

Acceptable alternative dosing schedules include—
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim three times a week (e.g., Monday, Wednesday, Friday) {94}.

Oral, 400 mg of sulfamethoxazole and 80 mg of trimethoprim once a day. {94}

[ HIV-related infection in Africa (prophylaxis)]1
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim once a day{172}{173}{174}.

Usual pediatric dose
Antibacterial (systemic)

Infants up to 2 months of age:
Use is not recommended since sulfonamides may cause kernicterus in neonates.

{03}{168}{169}{170}{171}

Infants 2 months of age and over:
Infants and children up to 40 kg of body weight—Oral, 20{168}{170} to 30 mg of sulfamethoxazole and 4 {168}{170}to 6 mg of trimethoprim per kg of body weight every twelve hours. {03}{58}

Children 40 kg of body weight and over—See Usual adult and adolescent dose.

Antiprotozoal

5. SPONSOR

5.1 Quality Assurance and Quality Control

5.1.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).

5.1.2 The sponsor is responsible for securing agreement from every involved parties to ensure direct access (see 1.21) to every trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.

5.1.3 Quality control should be applied to each stage of data handling to ensure that every data are dependable and own been processed correctly.

5.1.4 Agreements, made by the sponsor with the investigator/institution and any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate agreement.

5.2 Contract Research Organization (CRO)

5.2.1 A sponsor may transfer any or every of the sponsor’s trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.

5.2.2 Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing.

5.2.3 Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.

5.2.4 Every references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions of a sponsor.

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5.3 Medical Expertise

The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, exterior consultant(s) may be appointed for this purpose.

5.4 Trial Design

5.4.1 The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout every stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.

5.4.2 For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see 6.), the ICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate ICH guidance on trial design, protocol and conduct.

5.5 Trial Management, Data Handling, and Record Keeping

5.5.1 The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.

5.5.2 The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The IDMC should own written operating procedures and maintain written records of every its meetings.

5.5.3 When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:

a. Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e., validation).

b. Maintains SOPs for using these systems.

c. Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data (i.e., maintain an audit trail, data trail, edit trail).

d. Maintain a security system that prevents unauthorized access to the data.

e. Maintain a list of the individuals who are authorized to make data changes (see 4.1.5 and 4.9.3).

f. Maintain adequate backup of the data.

g. Safeguard the blinding, if any (e.g., maintain the blinding during data entry and processing).

5.5.4 If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data.

5.5.5 The sponsor should use an unambiguous subject identification code (see 1.58) that allows identification of every the data reported for each subject.

5.5.6 The sponsor, or other owners of the data, should retain every of the sponsor-specific essential documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical Trial).

5.5.7 The sponsor should retain every sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the product is approved, and/or where the sponsor intends to apply for approval(s).

5.5.8 If the sponsor discontinues the clinical development of an investigational product (i.e., for any or every indications, routes of istration, or dosage forms), the sponsor should maintain every sponsor-specific essential documents for at least 2 years after formal discontinuation or in conformance with the applicable regulatory requirement(s).

5.5.9 If the sponsor discontinues the clinical development of an investigational product, the sponsor should notify every the trial investigators/institutions and every the regulatory authorities.

5.5.10 Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s).

5.5.11 The sponsor-specific essential documents should be retained until at least 2 years after the final approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years own elapsed since the formal discontinuation of clinical development of the investigational product.

These documents should be retained for a longer period however if required by the applicable regulatory requirement(s) or if needed by the sponsor.

5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed.

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5.6 Investigator Selection

5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s).

Each investigator should be qualified by training and experience and should own adequate resources (see 4.1, 4.2) to properly conduct the trial for which the investigator is selected. If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multicentre trials, their organization and/or selection are the sponsor’s responsibility.

5.6.2 Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator’s Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.

5.6.3 The sponsor should obtain the investigator’s/institution’s agreement:

a. to conduct the trial in compliance with GCP, with the applicable regulatory requirement(s) (see 4.1.3), and with the protocol agreed to by the sponsor and given approval/favourable opinion by the IRB/IEC (see 4.5.1);

b. to comply with procedures for data recording/reporting;

c.

What is responsible for a drug allergy

to permit monitoring, auditing and inspection (see 4.1.4) and

d. to retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed (see 4.9.4 and 5.5.12).

The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.

5.7 Allocation of Duties and Functions

Prior to initiating a trial, the sponsor should define, establish, and allocate every trial-related duties and functions.

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5.8 Compensation to Subjects and Investigators

5.8.1 If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.

5.8.2 The sponsor’s policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).

5.8.3 When trial subjects get compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).

5.9 Financing

The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.

5.10 Notification/Submission to Regulatory Authority(ies)

Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the applicable regulatory requirement(s)) should submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission (as required by the applicable regulatory requirement(s))to start the trial(s). Any notification/submission should be dated and contain sufficient information to identify the protocol.

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5.11 Confirmation of Review by IRB/IEC

5.11.1 The sponsor should obtain from the investigator/institution:

a.

The name and address of the investigator’s/institution’s IRB/IEC.

b. A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations.

c. Documented IRB/IEC approval/favourable opinion and, if requested by the sponsor, a current copy of protocol, written informed consent form(s) and any other written information to be provided to subjects, subject recruiting procedures, and documents related to payments and compensation available to the subjects, and any other documents that the IRB/IEC may own requested.

5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s) in any aspect of the trial, such as modification(s) of the protocol, written informed consent form and any other written information to be provided to subjects, and/or other procedures, the sponsor should obtain from the investigator/ institution a copy of the modification(s) made and the date approval/favourable opinion was given by the IRB/IEC

5.11.3 The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC re-approvals/re-evaluations with favourable opinion, and of any withdrawals or suspensions of approval/ favourable opinion.

5.12 Information on Investigational Product(s)

5.12.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied.

5.12.2 The sponsor should update the Investigator’s Brochure as significant new information becomes available (see 7.

Investigator’s Brochure).

5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)

5.13.1 The sponsor should ensure that the investigational product(s) (including athletic comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In addition, the labelling should comply with applicable regulatory requirement(s).

5.13.2 The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions (e.g., protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any.

The sponsor should inform every involved parties (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.

5.13.3 The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.

5.13.4 In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding.

5.13.5 If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials.

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5.14 Supplying and Handling Investigational Product(s)

5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s).

5.14.2 The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains every required documentation (e.g., approval/favourable opinion from IRB/IEC and regulatory authority(ies)).

5.14.3 The sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof.

The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).

5.14.4 The sponsor should:

a. Ensure timely delivery of investigational product(s) to the investigator(s).

b. Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s) (see 8.

Essential Documents for the Conduct of a Clinical Trial).

c. Maintain a system for retrieving investigational products and documenting this retrieval (e.g., for deficient product recall, reclaim after trial completion, expired product reclaim).

d. Maintain a system for the position of unused investigational product(s) and for the documentation of this disposition.

5.14.5 The sponsor should:

a. Take steps to ensure that the investigational product(s) are stable over the period of use.

b.

Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are finish or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.

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5.15 Record Access

5.15.1 The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection.

5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.

5.16 Safety Information

5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).

5.16.2 The sponsor should promptly notify every concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC’s approval/favourable opinion to continue the trial.

5.17 Adverse Drug Reaction Reporting

5.17.1 The sponsor should expedite the reporting to every concerned investigator(s)/institution(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of every adverse drug reactions (ADRs) that are both serious and unexpected.

5.17.2 Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.

5.17.3 The sponsor should submit to the regulatory authority(ies) every safety updates and periodic reports, as required by applicable regulatory requirement(s).

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5.18 Monitoring

5.18.1 Purpose
The purposes of trial monitoring are to verify that:

a. The rights and well-being of human subjects are protected.

b. The reported trial data are precise, finish, and verifiable from source documents.

c. The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).

5.18.2 Selection and Qualifications of Monitors

a.

Monitors should be appointed by the sponsor.

b. Monitors should be appropriately trained, and should own the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.

c. Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).

5.18.3 Extent and Nature of Monitoring
The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring.

The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance can guarantee appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.

5.18.4 Monitor’s Responsibilities
The monitor(s) in accordance with the sponsor’s requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site:

a.

Acting as the main line of communication between the sponsor and the investigator.

b. Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) and remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate throughout the trial period.

c. Verifying, for the investigational product(s):

i. That storage times and conditions are acceptable, and that supplies are sufficient throughout the trial

ii.

That the investigational product(s) are supplied only to subjects who are eligible to get it and at the protocol specified dose(s).

iii. That subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s).

iv. That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately.

v. That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.

d. Verifying that the investigator follows the approved protocol and every approved amendment(s), if any.

e. Verifying that written informed consent was obtained before each subject’s participation in the trial.

f. Ensuring that the investigator receives the current Investigator’s Brochure, every documents, and every trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s).

g. Ensuring that the investigator and the investigator’s trial staff are adequately informed about the trial.

h. Verifying that the investigator and the investigator’s trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and own not delegated these functions to unauthorized individuals.

i. Verifying that the investigator is enrolling only eligible subjects.

j. Reporting the subject recruitment rate.

k. Verifying that source documents and other trial records are precise, finish, kept up-to-date and maintained.

l. Verifying that the investigator provides every the required reports, notifications, applications, and submissions, and that these documents are precise, finish, timely, legible, dated, and identify the trial.

m.

What is responsible for a drug allergy

Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. The monitor specifically should verify that:

i. The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents.

ii. Any dose and/or therapy modifications are well documented for each of the trial subjects.

iii. Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs.

iv. Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs.

What is responsible for a drug allergy

v. Every withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs.

n. Informing the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialled by the investigator or by a member of the investigator’s trial staff who is authorized to initial CRF changes for the investigator. This authorization should be documented.

o. Determining whether every adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s).

p. Determining whether the investigator is maintaining the essential documents (see 8. Essential Documents for the Conduct of a Clinical Trial).

q.

What is responsible for a drug allergy

Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.

5.18.5 Monitoring Procedures
The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial.

5.18.6 Monitoring Report

a. The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication.

b. Reports should include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted.

c. Reports should include a summary of what the monitor reviewed and the monitor’s statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance.

d. The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated representative.

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5.19 Audit
If or when sponsors act out audits, as part of implementing quality assurance, they should consider:

5.19.1 Purpose
The purpose of a sponsor’s audit, which is independent of and separate from routine monitoring or quality control functions, should be to assess trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.

5.19.2 Selection and Qualification of Auditors

a.

The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.

b. The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.

5.19.3 Auditing Procedures

a. The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor’s written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.

b. The sponsor’s audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).

c. The observations and findings of the auditor(s) should be documented.

d.To preserve the independence and worth of the audit function, the regulatory authority(ies) should not routinely request the audit reports.

Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.

e. When required by applicable law or regulation, the sponsor should provide an audit certificate.

5.20 Noncompliance

5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor’s staff should lead to immediate action by the sponsor to secure compliance.

5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator’s/institution’s participation in the trial. When an investigator’s/institution’s participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies).

5.21 Premature Termination or Suspension of a Trial

If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension.

The IRB/IEC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s).

5.22 Clinical Trial/Study Reports

Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory requirement(s).

The sponsor should also ensure that the clinical trial reports in marketing applications meet the standards of the ICH Guideline for Structure and Content of Clinical Study Reports. (NOTE: The ICH Guideline for Structure and Content of Clinical Study Reports specifies that abbreviated study reports may be acceptable in certain cases.)

5.23 Multicentre Trials

For multicentre trials, the sponsor should ensure that:

5.23.1 Every investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), and given approval/favourable opinion by the IRB/IEC.

5.23.2 The CRFs are designed to capture the required data at every multicentre trial sites.

For those investigators who are collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data.

5.23.3 The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial.

5.23.4 Every investigators are given instructions on following the protocol, on complying with a uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs.

5.23.5 Communication between investigators is facilitated.

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In most cases, people with allergies develop mild to moderate symptoms, such as watery eyes, a runny nose or a rash. But sometimes, exposure to an allergen can cause a life-threatening allergic reaction known as anaphylaxis. This severe reaction happens when an over-release of chemicals puts the person into shock. Allergies to food, insect stings, medications and latex are most frequently associated with anaphylaxis.

A second anaphylactic reaction, known as a biphasic reaction, can happen as endless as 12 hours after the initial reaction.

Call 911 and get to the nearest emergency facility at the first sign of anaphylaxis, even if you own already istered epinephrine, the drug used to treat severe allergic reactions.

Just because an allergic person has never had an anaphylactic reaction in the past to an offending allergen, doesn’t mean that one won’t happen in the future. If you own had an anaphylactic reaction in the past, you are at risk of future reactions.

What’s really behind ‘gluten sensitivity’?

By Kelly Servick

The patients weren’t crazy—Knut Lundin was certain of that. But their ailment was a mystery. They were convinced gluten was making them ill. Yet they didn’t own celiac disease, an autoimmune reaction to that often-villainized tangle of proteins in wheat, barley, and rye.

And they tested negative for a wheat allergy. They occupied a medical no man’s land.

About a decade ago, gastroenterologists love Lundin, based at the University of Oslo, came across more and more of those enigmatic cases. «I worked with celiac disease and gluten for so numerous years,» he says, «and then came this wave.» Gluten-free choices began appearing on restaurant menus and creeping onto grocery store shelves. By 2014, in the United States alone, an estimated 3 million people without celiac disease had sworn off gluten.

It was simple to assume that people claiming to be «gluten sensitive» had just been roped into a food fad.

«Generally, the reaction of the gastroenterologist [was] to tell, ‘You don’t own celiac disease or wheat allergy. Goodbye,’» says Armin Alaedini, an immunologist at Columbia University. «A lot of people thought this is perhaps due to some other [food] sensitivity, or it’s in people’s heads.»

But a little community of researchers started searching for a link between wheat components and patients’ symptoms—commonly abdominal pain, bloating, and diarrhea, and sometimes headaches, fatigue, rashes, and joint pain. That wheat really can make nonceliac patients ill is now widely accepted.

But that’s about as far as the agreement goes.

As data trickle in, entrenched camps own emerged. Some researchers are convinced that numerous patients own an immune reaction to gluten or another substance in wheat—a nebulous illness sometimes called nonceliac gluten sensitivity (NCGS).

Others believe most patients are actually reacting to an excess of poorly absorbed carbohydrates present in wheat and numerous other foods. Those carbohydrates—called FODMAPs, for fermentable oligosaccharides, disaccharides, monosaccharides, and polyols—can cause bloating when they ferment in the gut. If FODMAPs are the primary culprit, thousands of people may be on gluten-free diets with the support of their doctors and dietitians but without excellent reason.

Those competing theories were on display in a session on wheat sensitivity at a celiac disease symposium held at Columbia in March.

In back-to-back talks, Lundin made the case for FODMAPs, and Alaedini for an immune reaction. But in an irony that underscores how muddled the field has become, both researchers started their quests believing something completely different.

Known wheat-related illnesses own clear mechanisms and markers. People with celiac disease are genetically predisposed to launch a self-destructive immune response when a component of gluten called gliadin penetrates their intestinal lining and sets off inflammatory cells in the tissue under.

People with a wheat allergy reply to wheat proteins by churning out a class of antibodies called immunoglobulin E that can set off vomiting, itching, and shortness of breath. The puzzle, for both doctors and researchers, is patients who lack both the telltale antibodies and the visible damage to their intestines but who feel genuine relief when they cut out gluten-containing food.

Some doctors own begun to approve and even recommend a gluten-free diet. «Ultimately, we’re here not to do science, but to improve quality of life,» says Alessio Fasano, a pediatric gastroenterologist at Massachusetts General Hospital in Boston who has studied NCGS and written a book on living gluten-free.

«If I own to throw bones on the ground and glance at the moon to make somebody better, even if I don’t understand what that means, I’ll do it.»

Like numerous doctors, Lundin believed that (fad dieters and superstitious eaters aside) some patients own a genuine wheat-related ailment. His group helped dispel the notion that NCGS was purely psychosomatic. They surveyed patients for unusual levels of psychological distress that might express itself as physical symptoms. But the surveys showed no differences between those patients and people with celiac disease, the team reported in 2012.

As Lundin bluntly puts it: «We know they are not crazy.»

Still, skeptics worried that the field had seized on gluten with shaky evidence that it was the culprit. After every, nobody eats gluten in isolation. «If we did not know about the specific role of gluten in celiac disease, we would never own thought gluten was responsible for [NCGS],» says Stefano Guandalini, a pediatric gastroenterologist at the University of Chicago Medical Middle in Illinois.

«Why blame gluten?»

Defenders of NCGS generally acknowledge that other components of wheat might contribute to symptoms. In 2012, a group of proteins in wheat, rye, and barley called amylase trypsin inhibitors emerged as a potential offender, for example, after a team led by biochemist Detlef Schuppan of Johannes Gutenberg University Mainz in Germany (then at Harvard Medical School in Boston) reported that those proteins can provoke immune cells.

But without biological markers to identify people with NCGS, researchers own relied on self-reported symptoms measured through a «gluten challenge»: Patients rate how they feel before and after cutting out gluten.

Then doctors reintroduce gluten or a placebo—ideally disguised in indistinguishable pills or snacks—to see whether the symptoms tick back up.

Alaedini has recently hit on a more objective set of possible biological markers—much to his own surprise. «I entered this completely as a skeptic,» he says. Over his career, he has gravitated toward studying spectrum disorders, in which diverse symptoms own yet to be united under a clear biological cause—and where public misinformation abounds. His team published a study in 2013, for example, that debunked the favorite suggestion that children with autism had high rates of Lyme disease.

«I do studies [where] there is a void,» he says.

In NCGS, Alaedini saw another poorly defined spectrum disorder. He did accept that patients without celiac disease might somehow be sensitive to wheat, on the basis of several trials that measured symptoms after a blinded challenge. But he was not convinced by previous studies claiming that NCGS patients were more likely than other people to own certain antibodies to gliadin. Numerous of those studies lacked a healthy control group, he says, and relied on commercial antibody kits that gave murky and inconsistent readings.

In 2012, he contacted researchers at the University of Bologna in Italy to obtain blood samples from 80 patients their team had identified as gluten sensitive on the basis of a gluten challenge.

He wanted to test the samples for signs of a unique immune response—a set of signaling molecules diverse from those in the blood of healthy volunteers and celiac patients. He wasn’t optimistic. «I thought if we were going to see something, love with a lot of spectrum conditions that I own looked at, we would see little differences.»

The results shocked him. Compared with both healthy people and those with celiac, these patients had significantly higher levels of a certain class of antibodies against gluten that propose a short-lived, systemic immune response.

That didn’t mean gluten itself was causing disease, but the finding hinted that the barrier of those patients’ intestines might be faulty, allowing partially digested gluten to get out of the gut and interact with immune cells in the blood. Other elements—such as immune response–provoking bacteria—also might be escaping. Certain enough, the team found elevated levels of two proteins that indicate an inflammatory response to bacteria. And when 20 of the same patients spent 6 months on a gluten-free diet, their blood levels of those markers declined.

For Alaedini, the beginnings of a mechanism emerged: Some still-unidentified wheat component prompts the intestinal lining to become more permeable.

(An imbalance in gut microbes might be a predisposing factor.) Components of bacteria then seem to sneak past immune cells in the underlying intestinal tissue and make their way to the bloodstream and liver, prompting inflammation.

«This is a genuine condition, and there can be objective, biological markers for it,» Alaedini says. «That study changed a lot of minds, including my own.»

The study also impressed Guandalini, a longtime skeptic about the role of gluten. It «opens the way to finally reach an identifiable marker for this condition,» he says.

But others see the immune-response explanation as a red herring.

To them, the primary villain is FODMAPs. The term, coined by gastroenterologist Peter Gibson at Monash University in Melbourne, Australia, and his team, encompasses a smorgasbord of common foods. Onions and garlic; legumes; milk and yogurt; and fruits including apples, cherries, and mangoes are every high in FODMAPs. So is wheat: Carbs in wheat called fructans can account for as much as half of a person’s FODMAP intake, dietitians in Gibson’s group own estimated. The team found that those compounds ferment in the gut to cause symptoms of irritable bowel syndrome, such as abdominal pain, bloating, and gas.

Gibson has endless been skeptical of studies implicating gluten in such symptoms, arguing that those findings are hopelessly clouded by the nocebo effect, in which the mere expectation of swallowing the dreaded ingredient worsens symptoms.

His team found that most patients couldn’t reliably distinguish pure gluten from a placebo in a blinded test. He believes that numerous people feel better after eliminating wheat not because they own calmed some intricate immune reaction, but because they’ve reduced their intake of FODMAPs.

Lundin, who was firmly in the immune-reaction camp, didn’t believe that FODMAPs could explain away every his patients. «I wanted to show that Peter was wrong,» he says. During a 2-week sabbatical in the Monash lab, he found some quinoa-based snack bars designed to disguise the taste and texture of ingredients.

«I said, ‘We’re going to take those muesli bars and we’re going to do the perfect study.’»

His team recruited 59 people on self-instituted gluten-free diets and randomized them to get one of three indistinguishable snack bars, containing isolated gluten, isolated FODMAP (fructan), or neither. After eating one type of bar daily for a week, they reported any symptoms. Then they waited for symptoms to resolve and started on a diverse bar until they had tested every three.

Before analyzing patient responses, Lundin was confident that gluten would cause the worst symptoms.

But when the study’s blind was lifted, only the FODMAP symptoms even cleared the bar for statistical significance. Twenty-four of the 59 patients had their highest symptom scores after a week of the fructan-laced bars. Twenty-two responded most to the placebo, and just 13 to gluten, Lundin and his collaborators—who included Gibson—reported final November in the journal Gastroenterology. Lundin now believes FODMAPs explain the symptoms in most wheat-avoiding patients. «My main reason for doing that study was to discover out a excellent method of finding gluten-sensitive individuals,» he says. «And there were none.

And that was fairly amazing.»

At the Columbia meeting, Alaedini and Lundin went head to head in consecutive talks titled «It’s the Wheat» and «It’s FODMAPS.» Each has a list of criticisms of the other’s study. Alaedini contends that by recruiting broadly from the gluten-free population, instead of finding patients who reacted to wheat in a challenge, Lundin likely failed to include people with a true wheat sensitivity. Extremely few of Lundin’s subjects reported symptoms exterior the intestines, such as rash or fatigue, that might point to a widespread immune condition, Alaedini says.

And he notes that the increase in patients’ symptoms in response to the FODMAP snacks was just barely statistically significant.

Lundin, meanwhile, points out that the patients in Alaedini’s study didn’t go through a blinded challenge to check whether the immune markers he identified really spiked in response to wheat or gluten. The markers may not be specific to people with a wheat sensitivity, Lundin says.

Despite the adversarial titles of their talks, the two researchers discover a lot of common ground.

Alaedini agrees that FODMAPs explain some of the wheat-avoidance phenomenon. And Lundin acknowledges that some little population may really own an immune reaction to gluten or another component of wheat, though he sees no excellent way to discover them.

After the meeting, Elena Verdù, a gastroenterologist at McMaster University in Hamilton, Canada, puzzled over the polarization of the field. «I don’t understand why there is this need to be so dogmatic about ‘it is this, it is not that,’» she says.

She worries that the scientific confusion breeds skepticism toward people who avoid gluten for medical reasons.

When she dines with celiac patients, she says, waiters sometimes meet requests for gluten-free food with smirks and questions. Meanwhile, the conflicting messages may send nonceliac patients below a food-avoidance rabbit hole. «Patients are withdrawing gluten first, then lactose, and then FODMAPs—and then they are on a really, really poor diet,» she says.

But Verdù believes careful research will ultimately break through the superstitions. She is president of the North American Society for the Study of Celiac Disease, which this year awarded its first grant to study nonceliac wheat sensitivity.

She’s hopeful that the search for biomarkers love those Alaedini has proposed will show that inside the monolith of gluten avoidance lurk multiple, nuanced conditions. «It will be difficult,» she says, «but we are getting closer.»

doi:10.1126/science.aau2590


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