Home

Search CDDW Abstracts

CLICK HERE FOR ENTOCORT CAPSULES PRODUCT MONOGRAPH

CLICK HERE FOR ABSTRACTS

CLICK HERE FOR LOSEC PI

 

PRODUCT MONOGRAPH

entocort_logo.gif (10107 bytes)

(budesonide)

Enema

0.02 mg/mL

Glucocorticosteroid for the Treatment of Distal Ulcerative Colitis


DATE OF PREPARATION:

February 15, 2000

DATE OF REVISION:

September 7, 2000


Previously Control # 065207

ENTOCORT« is a trademark, the property of the AstraZeneca group.

 

PRODUCT MONOGRAPH

NAME OF DRUG

entocort_logo.gif (10107 bytes)

(budesonide)

Enema

0.02 mg/mL

THERAPEUTIC CLASSIFICATION

Glucocorticosteroid for the treatment of distal ulcerative colitis.

ACTIONS AND CLINICAL PHARMACOLOGY

The active ingredient of ENTOCORT, budesonide, is a potent non-halogenated synthetic glucocorticosteroid with strong topical and weak systemic effects.

ENTOCORT has a high topical anti-inflammatory potency. It undergoes an extensive degree (approximately 90%) of biotransformation in the liver to metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6b-hydroxybudesonide and 16a-hydroxyprednisolone, is less than 1% of that of budesonide.

The favourable separation between topical anti-inflammatory and systemic effect is due to strong glucocorticosteroid receptor affinity and an effective first pass metabolism with a short half-life.

A glucocorticosteroid with such a profile is of particular importance for the local treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC). With regard to treatment of these diseases with glucocorticosteroids, it is essential to achieve a high local anti-inflammatory activity in the bowel wall with systemic side-effects, e.g. on the hypothalamic pituitary adrenal (HPA) axis function, as low as possible. At the recommended doses, budesonide enema causes no or small suppression of plasma cortisol.

Pharmacokinetics

Absorption in healthy subjects after rectal dosing of 2 mg budesonide low viscosity enema is rapid and essentially complete within 3 hours. The mean maximal plasma concentration after rectal administration is 3.0 ▒ 2.0 nmol/L, reached within 1.5 hours. Similar results are obtained in patients suffering from distal ulcerative colitis. The mean systemic availability after rectal dosing is 15 ▒ 12%. The plasma half-life is between 2 and 3 hours in adults.

INDICATIONS AND CLINICAL USE

ENTOCORT (budesonide) is indicated in the management of distal ulcerative colitis (rectum, sigmoid and descending colon).

CONTRAINDICATIONS

ENTOCORT (budesonide) is contraindicated for the following: 

  1. Local contraindications to the use of ENTOCORT include imminent bowel perforation as well as the probability of obstruction, abscess or other pyogenic infection, fresh intestinal anastomoses, extensive fistulas and sinus tracts

  2. Systemic or local bacterial, fungal or viral infections

  3. Known hypersensitivity to any of the ingredients

  4. Active tuberculosis

  5. Ocular herpes simplex, and acute psychosis

WARNINGS

Special care is demanded in treatment of patients transferred from systemic steroids to ENTOCORT (budesonide) as disturbances in the hypothalamic-pituitary-adrenal axis could be expected in these patients.

PRECAUTIONS

Glucocorticosteroids may mask some signs of infections and new infections may appear. A decreased resistance to localized infection has been observed during corticosteroid therapy. Viral infections such as chicken pox and measles can have a more serious or fatal course in patients on immunosuppressant corticosteroids. In adults who have not had these diseases, particular care should be taken to avoid exposure. If exposed to chicken pox or measles, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If chicken pox develops treatment with antiviral agents may be considered.

At recommended doses, budesonide enema causes no clinically important changes in basal plasma cortisol levels or in the response to stimulation with ACTH. The effects on morning plasma cortisol and adrenal function are significantly less compared with prednisolone enema 25 mg daily. However, knowledge with regard to treatment of the following conditions is limited and therefore cautioned: active or lateral peptic ulcer, osteoporosis, acute glomerulonephritis, myasthenia gravis, exanthematous diseases, diverticulitis, thrombophlebitis, psychic disturbances, diabetes, hypertension, hyperthyroidism, acute coronary disease, limited cardiac reserve and pregnancy. In such cases the benefits of a corticosteroid enema must be weighed against the risks.

There are still insufficient data on the long-term systemic effect of budesonide. With the recommended therapeutic doses, the risk/benefit ratio seems to be very low. However, as with any other glucocorticosteroid, patients should be carefully followed up for systemic adverse effects. During long-term therapy, pituitary-adrenal function and haematological status should be periodically assessed.

Some patients feel unwell in a non-specific way during the withdrawal phase, e.g., pain in muscles and joints. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of systemic glucocorticosteroids is sometimes necessary.

Glucocorticosteroid enemas should be administered with caution in patients with severe ulcerative colitis because these patients are predisposed to perforations of the bowel wall.

Patients should be advised to inform subsequent physicians of the prior use of glucocorticosteroids.

Aggravation of diabetes mellitus or stimulation of manifestations of latent diabetes mellitus may be caused by corticosteroid therapy.

There may be an enhanced effect of budesonide in patients with liver cirrhosis and, as with other glucocorticosteroids, there may be enhanced effects in those with hypothyroidism. Reduced liver function may affect the elimination of corticosteroids. The intravenous pharmacokinetics of budesonide are, however, similar in cirrhotic patients and in healthy subjects. The pharmacokinetics after oral ingestion of budesonide were affected by compromised liver function as evidenced by increased systemic availability.

Glucocorticosteroid therapy may cause hyperacidity of peptic ulcer.

Acetylsalicylic acid should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

Glucocorticosteroids may cause elevation of intraocular pressure in glaucoma patients.

Usage During Pregnancy

Administration of ENTOCORT (budesonide) during pregnancy should be avoided unless there are compelling reasons. In experimental animal studies, budesonide was found to cross the placental barrier. Like other glucocorticosteroids, budesonide is teratogenic to rodent species. High doses of budesonide administered subcutaneously produced fetal malformations, primarily skeletal defects, in rabbits, rats, and in mice. The relevance of these findings to humans has not yet been established. In the absence of further studies in humans, budesonide should be used during pregnancy only if the potential benefits clearly outweigh the risk to the fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for hypoadrenalism.

Lactation

Glucocorticosteroids are secreted in human milk. It is not known whether budesonide would be secreted in human milk, but it is suspected to be likely. The use of ENTOCORT in nursing mothers requires that the possible benefits of the drug be weighed against the potential hazards to the mother, or infant.

Children

The safety and effectiveness of ENTOCORT in children have not been established, therefore use in this age group is not recommended.

Drug Interactions

To date, budesonide has not been observed to interact with other drugs used for the treatment of intestinal bowel diseases.

Cimetidine

The kinetics of budesonide were investigated in healthy subjects without and with cimetidine, 1000 mg daily. After a 4 mg oral dose the values of Cmax (nmol/L) and systemic availability (%) of budesonide without and with cimetidine (3.3 vs 5.1 nmol/L and 10 vs 12%, respectively) indicated a slight inhibitory effect on hepatic metabolism of budesonide, caused by cimetidine. This should be of little clinical importance.

Ketoconazole

Ketoconazole, a potent inhibitor of cytochrome P 450 3A, the main metabolic enzyme for corticosteroids, increases plasma levels of orally ingested budesonide.

Omeprazole

At recommended doses, omeprazole has no effect on the pharmacokinetics of oral budesonide.

ADVERSE REACTIONS

No major side effects attributable to the use of ENTOCORT (budesonide) have been reported. During clinical trials, the frequency of subjectively reported side effects in a total of 247 patients and healthy volunteers given 2 mg budesonide, once daily in the morning, was low.

The most common adverse reactions are gastrointestinal disturbances, e.g., flatulence, nausea, diarrhoea. These symptoms were reported in 23 of the 247 patients (9%) receiving 2 mg of budesonide. Psychiatric symptoms (insomnia, agitation, anxiety, depression, dysphoria, emotional lability, somnolence) were reported in 7 patients (3%) receiving 2 mg budesonide. Skin reactions (rash, urticaria) occurred in 5 patients (2%). Systemic effects of budesonide on the HPA-axis function were found to be dose-dependent. In rare cases, signs or symptoms of systemic glucocorticosteroid effects, including hypofunction of the adrenal gland, may occur with rectally administered glucocorticosteroids, probably depending on dose, treatment time, concomitant and previous glucocorticosteroid intake, and individual sensitivity. Rectal administration of high concentrations of budesonide (10 mg/dose) resulted in significant suppression of endogenous cortisol concentrations as measured by plasma and urinary cortisol levels. In patients in whom systemic steroids are reduced or stopped, withdrawal symptoms due to decreased systemic activity may occur.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Acute overdosage with ENTOCORT (budesonide), even in excessive doses, is not expected to be a clinical problem. When used chronically at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of ENTOCORT should be discontinued consistent with accepted procedures for discontinuing prolonged oral steroid therapy. However, the dosage form, enema, and the route of administration make any prolonged overdosage unlikely.

Occasional overdosing will not give any obvious symptoms in most cases but it will decrease the plasma cortisol level and increase the number and percentage of circulating neutrophils. The number and percentage of eosinophils will decrease concurrently. Stopping the treatment or decreasing the dose will abolish the induced effects.

Habitual overdosing may cause hypercorticism and hypothalamic-pituitary-adrenal suppression. Decreasing the dose or stopping the therapy will abolish these effects, although the restitution of the HPA-axis may be a slow process and during periods with pronounced physical stress (severe infections, trauma, surgical operations, etc.) it may be advisable to supplement with systemic steroids.

DOSAGE AND ADMINISTRATION

One ENTOCORT (budesonide) retention enema is given nightly to the patient for 4 weeks. If the patient is not in remission after 4 weeks, the treatment period may be prolonged to 8 weeks.

ENTOCORT enema is reconstituted by adding one dispersible tablet into the enema bottle, whereafter the bottle is vigorously shaken for at least 10 seconds or until the tablet is completely dissolved. The tablet will disintegrate rapidly and the suspension will turn slightly yellowish.

PHARMACEUTICAL INFORMATION

Drug Substance

Chemical Structure: image005.jpg (5818 bytes)
Generic Name:

 

Budesonide

 

Chemical Name:

 

Budesonide is a mixture of two isomers:
  1. Pregna-1,4-diene-3,20-dione, 16,17- butylidenebis(oxy)-11,21-dihydroxy-,[11▀,16a (R)]
  2. Pregna-1,4-diene-3,20-dione, 16,17- butylidenebis(oxy)-11,21-dihydroxy-,[11▀,16a (S)].
Molecular Formula:

 

C25H34O6

 

Molecular Weight:

 

430.5

 

Description: Budesonide is a non-halogenated glucocorticosteroid and consists of a 1:1 mixture of two epimers, 22R and 22S. It is a white to off-white crystalline powder and is freely soluble in chloroform, sparingly soluble in ethanol, practically insoluble in water and in heptane. Budesonide melts at 224 C to 231.5 C, with decomposition.

Composition 

Budesonide enema 0.02 mg/mL (I + II) consists of 2 components:

I Dispersible Tablet

 

1 tablet contains: Budesonide micronized 2.3 mg
Lactose anhydrous
Riboflavin-5-phosphate sodium
Lactose
Polyvidone, cross-linked
Colloidal silicon dioxide
Magnesium stearate
II Vehicle

 

1 mL contains: Sodium chloride
Methylparaben
Propylparaben
Water purified

Stability and Storage Recommendations

Store at 15-30 C. After preparation of the enema, the solution is intended for immediate use.

AVAILABILITY OF DOSAGE FORMS

ENTOCORT (budesonide) retention enema 0.02 mg/mL consists of 2 components: a dispersible tablet and a vehicle. The enema is reconstituted before use.

The volume of the reconstituted enema is 115 mL. Since the residual volume is about 15 mL, the dose administered to the patient is about 2 mg budesonide.

The tablets are provided in an aluminum blister package and the vehicle is in a polyethylene bottle equipped with a rectular nozzle.

Each carton contains 7 dispersible tablets and vehicle solutions.

Customer Inquiries: 1 800 668-6000

Trademarks herein are the property of the AstraZeneca group.

AstraZeneca Canada Inc.
Mississauga,
Ontario, L4Y 1M4

09/2000

PHARMACOLOGY

Animal Pharmacology

Budesonide exhibits typical glucocorticoid effects in that subcutaneous administration to adrenalectomized rats induced glycogen deposition in the liver, increased urinary volume and only slightly affected sodium excretion.

Whole body autoradiography in mice has shown budesonide and its metabolites to have a similar distribution pattern to other glucocorticosteroids with a high distribution to endocrine organs.

Data from preclinical investigations show a rapid elimination of the drug in all investigated species (rat, mouse, rabbit and dog). This rapid systemic elimination is attributed to extensive liver metabolism, mainly via oxidative and reductive pathways. No or insignificant metabolism of budesonide was found in target organs such as lung and skin. This is as a result of low amounts of the enzyme system (Cytochrome P450) which is responsible for the metabolism of budesonide in these organs.

Human Pharmacology

Pharmacodynamics

Mode of Action

The exact mechanism of action of GCS in the treatment of UC is not yet fully understood. Anti-inflammatory actions, such as blocking of inflammatory cell influx and inhibition of inflammatory mediator release by blockage of the arachidonic acid pathway, are probably important. There is evidence that for GCS enemas, the anti-inflammatory action is predominantly local.

Effect on Haematological Parameters

Glucocorticosteroids increase blood neutrophils and decrease blood basophils, eosinophils and lymphocytes within 4 to 6 hours after administration to healthy volunteers. These effects are due to a transient redistribution of cells, with the values returning to normal within 24 hours.

Pharmacokinetics

Absorption

The pharmacokinetics of budesonide after rectal dosing are summarized in the table below (mean and S.D. are given).

No. of Subjects/Patients

Diagnosis

Dose (mg)

Polysorbate

Syst. Avail. (%)

Cmax
(nmol/L)

Tmax
(h)

5

U.C.1

2

+

-

2.5 ▒ 1.4

1.5 ▒ 0.9

15

Healthy

2

-

15 12

3.0 ▒ 2.0

1.3 ▒ 0.4

15

Healthy

2

+

16 11

3.3 ▒ 1.9

1.3 ▒ 0.3

24

U.C.

2

-

-

2.1 ▒ 1.22

1.3 ▒ 0.62

24

U.C.

2

-

-

2.5 ▒ 1.73

1.2 ▒ 0.43

1Ulcerative colitis
2After the first dose
3After 4 weeks' treatment

The volume of distribution of budesonide (3 L/kg) is large and the plasma protein binding (88%) is extensive compared with other synthetic GCS. The free volume of distribution (i.e., the ratio between volume of distribution and free plasma) is high for budesonide. This reflects a high tissue affinity of the compound.

Metabolism and Excretion

The half-life of budesonide after intravenous administration is 2-3 h in adults and shorter, 1.5 h, in children. After rectal dosing, the plasma half-life is almost identical to that seen after intravenous dosing. Absorption in healthy subjects following a rectal dose of 2 mg budesonide enema is rapid and essentially complete within 3 hours. The mean maximal plasma concentration after rectal administration is 3.0 2.0 nmol/L reached within 1.5 hours. Similar results are obtained in patients suffering from distal ulcerative colitis.

The systemic clearance of budesonide (0.9 - 1.4 L/min) is high compared with other GCS. After oral dosing, the drug is rapidly and extensively absorbed, but the systemic availability is only 10-13%. This is similar to budesonide systemic availability after rectal dosing (15 12%). The between-subject variability in systemic availability is greater after rectal than after oral dosing. Possible reasons for this may be, e.g., different hepatic by-pass due to inter-individual differences in rectal venous drainage and/or microbial degradation of budesonide. These differences are, however, probably of minor clinical importance regarding the efficacy since the effect of budesonide is mainly topical. The favourable topical antiinflammatory activity to systemic effect ratio is most probably due to its high glucocorticoid receptor affinity and high first pass metabolism with a short half-life.

In human volunteers who inhaled tritiated budesonide, 31.8 ▒ 7.5% of the discharged radioactivity was recovered in the urine (within 96 hours of administration) while during the same period, 15.1 ▒ 4.3% of the radioactivity could be recovered in the faeces. In those subjects who took the compound orally, 45.0 ▒ 5.0% was recovered in the urine, 29.6 ▒ 2.5% in the faeces. Virtually no unchanged budesonide is excreted in the urine.

In vitro studies with human liver have shown that budesonide is rapidly metabolized to more polar compounds than the parent drug. Two major metabolites have been isolated and identified as 6b hydroxybudesonide and 16a hydroxyprednisolone. The glucocorticoid activity of these two metabolites was at least 100-fold lower than the parent compound as shown in the rat ear edema test. No qualitative differences between the in vitro and in vivo metabolic patterns could be detected. Negligible biotransformation was observed in human lung and serum preparations.

TOXICOLOGY

A complete toxicological program (acute, chronic, reproduction, mutagenicity and carcinogenicity studies) has been performed with budesonide after various routes of administration, such as oral, subcutaneous, epicutaneous and inhalation. Most of the studies were performed in rats and dogs. No toxicological studies have been performed with budesonide, using rectal administration.

Acute Toxicity

The acute toxicity studies with budesonide after oral and subcutaneous administration are summarized in the table below.

Species

Sex

Route

LD50 (mg/kg) after 3 Weeks

Mouse

Male

s.c.

35 ▒ 18

Mouse

Mouse

Male

Female

p.o.

p.o.

> 800

> 800

Rat

Rat

Rat

Male

Female

Male

s.c.

s.c.

p.o.

15.1 ▒ 4.4

20.3 ▒ 7.1

400

Surviving animals exhibited a marked decrease in body weight gain.

Toxicity After Repeated Administration

Table 2 summarizes the toxicity information from studies in which rats, rabbits and dogs received repeated oral, inhalation and subcutaneous administration of budesonide.

Teratology and Reproduction Studies

Effects on Pregnancy

Rat

Daily doses of 20, 100, and 500 mg/kg body mass were administered subcutaneously to pregnant rats during days 6-15 of gestation. In the high dose group, all of the rats showed a deteriorated general condition including piloerection, drowsiness, decreased food consumption and decreased body mass gain. Fetal loss was increased and pup masses decreased in comparison to the control group. The frequency of fetal abnormalities was also increased. Doses in excess of 100 mg/kg must be considered teratogenic in the rat.

Daily doses of 0.01, 0.05 and 0.1 - 0.25 mg/kg were administered by inhalation to pregnant rats during days 6-15 of gestation. At the highest dose a slight significant reduction in fetal weight gain was observed, but there was no evidence of any effect on fetal development attributable to budesonide at any dose level.

Rabbit

Daily doses of 5, 25, and 125 mg/kg body mass were administered subcutaneously during days 6-18 of gestation. In the low and medium dose groups, food consumption and body mass gain were decreased during the fourth gestational week. Some does also showed signs of diarrhea and vaginal bleeding. In the high dose group, all does aborted at the end of the gestation period. In the medium dose group, a marked increase in the frequency of abnormalities, mainly skeletal defects, was observed. Most commonly, defects were skull and vertebral abnormalities.

Effects on Fertility and General Reproductive Performance

Rat

To evaluate the effect of budesonide on fertility and general reproductive performance, daily doses of 0.01, 0.05, 0.19 mmol/kg were given subcutaneously to males for 9 weeks prior to and throughout mating. Females received the same doses for two weeks before, throughout gestation and up to 21 days postpartum. The offspring of the high dose group showed a decrease of peri- and post-natal viability. Dams showed a decrease in body mass gain.

Mutagenicity Studies

Budesonide showed no mutagenic activity in the Ames Salmonella/microsome plate test or in the mouse micronucleus test.

Table 2. Toxicity after repeated administration of budesonide to rats, rabbits and dogs.

Animal  

No. of Dose Groups

Daily Dose Levels Route of Administration Duration Toxic Effects
Species Strain Number and Sex Per Group   mg/kg mg/animal      

Rat

Sprague-
Dawley

6 males

6 females

4

0.05

0.5

5.0

50.0

 

p.o.

1 month

Atrophy of adrenal gland and lymphoid system. Gastric ulceration.

Rat

Wistar

10 males

10 females

3

0.02

0.10

0.2-0.5

 

inhalation

3 months

Hair loss dose related. Reduction in lymphocytes, leukocytes, increase in neutrophils. In high dose group, reduced adrenal, thymic, splenic and hepatic weights. No pulmonary impairment observed.

Rat

Wistar

40 males

40 females

3

0.005

0.01

0.05

 

inhalation

12 months

As above.

Rabbit

New Zealand White

3 males

3 females

2

 

0.025

0.1

s.c.

1 month

High dose caused slight liver mass increase, slight decrease in adrenal mass, thymal regression.

Dog

Beagle

1 male

1 female

3

0.01

0.1

1.0

 

p.o.

1 month

High dose - typical steroid effects - adrenal, lymphoid system atrophy, increased fat in myocardium, glycogen in liver.

Dog

Beagle

2 males

2 females

3

0.02

0.06

0.2

 

inhalation

6 weeks

High dose - induced thymal atrophy, adrenal atrophy. No changes in respiratory system observed.

Dog

Beagle

5 males

5 females

3

 

0.20

0.60

2.00

inhalation

6 months

High dose - decreased plasma cortisol, cortical atrophy of the adrenal gland, thymal regression. Slight visceral obesity.

Dog

Beagle

5 males

5 females

3

 

0.20

0.60

2.00

inhalation

12 months

High dose - obesity, alopecia, females showed no evidence of estrous cycle. Systemic steroid effects - lymphoid and adrenal atrophy.
All effects observed were consistent with those expected during prolonged corticosteroid exposure.

Carcinogenicity

The carcinogenic potential of budesonide was evaluated in long term mouse and rat studies.

Chronic Drinking Water Study in Mice

Budesonide was administered in the drinking water for 91 weeks to three groups of CD« -1 mice at dose levels of 10, 50 and 200 mg/kg/day.

A statistically significant dose-related decrease in survival was noted for the males only. All other evaluation criteria were comparable in all groups. Upon microscopic examination, a variety of spontaneous lesions was observed which were not related to treatment. No carcinogenic effect was present.

Chronic Drinking Water Study (104 Weeks) with Budesonide in Rats

Three rat carcinogenicity studies have been performed. In the first study, budesonide was administered for 104 weeks in doses of 10, 25 and 50 mg/kg/day.

A small but statistically significant increase in gliomas was noted in male animals from the high dose group. These results were considered equivocal since the S-D rat is very variable with regard to spontaneous glioma incidence.

To elucidate these results, two further 104 week carcinogenicity studies with budesonide 50 mg/kg/day were performed, one using male S-D rats, and one using male Fischer rats (which have a lower and less variable incidence of gliomas).

Prednisolone and triamcinolone acetonide were used as reference glucocorticoids in both studies.

The results from these new carcinogenicity studies in male rats did not demonstrate an increased glioma incidence in budesonide treated animals, as compared to concurrent controls or reference glucocorticosteroid treated groups.

Compared with concurrent control male S-D rats there was also an increased incidence of liver tumours in the mid- and high-dose groups in the original study. This finding was confirmed in all three steroid groups (budesonide, prednisolone, triamcinolone acetonide) in the repeat study in male S-D rats thus indicating a class effect of glucocorticosteroids.

Toxicological Effects on the Gastrointestinal Tract

There are few apparent toxicological effects of low doses of budesonide noted on the gastrointestinal tract which, together with the liver, is a body organ system that will be exposed to high concentrations of budesonide after oral and/or rectal administration of the drug.

Oral administration of budesonide to rats for 1 month disclosed thymus atrophy at 50 mg/kg. At 500 mg/kg atrophy of spleen and adrenals was also noted as well as fat deposition in the liver, effects typical of a glucocorticoid. No adverse effects on the gastrointestinal tract were noted. However, at 5000 mg/kg ulcerations and bleeding of the gastrointestinal tract were noted as well as pronounced systemic toxicity.

Administration of budesonide, in the drinking water, to rats for 3 months, revealed at necropsy stomach changes including raised white areas or nodules, dark ulcer-like areas, dark or dark-red foci and dark depressed areas among the female treated rats (50-700 mg/kg) and in one high-dosed male out of ten (700 mg/kg). No changes were noted in the control animals (both sexes). Similar stomach changes were also found in a three-month drinking water study in mice. No changes were noted at 10 mg/kg but these stomach changes were observed at 50 mg/kg in both sexes. However, no stomach lesions were reported among the high dosed male mice (700 mg/kg). A few control animals were also affected.

Histological examination was not performed in either of these two studies. In a 12-month inhalation study (mainly oral/gastrointestinal deposition and absorption) in rats, effects such as atrophy of lymphoid organs and reduced lymphocyte counts were noted at 50 mg/kg (high dose). Histological examination disclosed the absence of bile duct hyperplasia of the liver. This is generally a glucocorticoid effect. Bile duct hyperplasia is also a normal finding in the senescent rat. There were no adverse effects on the gastrointestinal tract at 50 mg/kg.

Budesonide given orally to dogs for 1 month disclosed atrophy of adrenals and lymphoid organs at 100 mg/kg but not at 10 mg/kg. At 100 mg/kg there was a slight liver enlargement with increased glycogen deposition. No adverse effects were noted on the gastrointestinal tract. A 12-month oral inhalation study in dogs (doses between 20-200 mg/kg) disclosed a dose-related reduction in plasma cortisol. Atrophy of lymphoid organs and adrenals was found at 60 and 200 mg/kg. Increased liver weight and glycogen deposition were obtained at 200 mg/kg. There were no adverse effects on the gastrointestinal tract at any dose level.

BIBLIOGRAPHY

Brogden RN, McTavish D.
Budesonide: An updated review of its pharmacological properties and therapeutic efficacy in asthma and rhinitis.
Drugs 1992; 44 (3): 375-407.

Danielsson ┼, Hellers G, Lyrenńs E, L÷fberg R, Nilsson ┼, Olsson O, Olsson S-┼, Persson T, Salde L, Naesdal J, Stenstarn M, WillÚn R.
A controlled randomized trial of budesonide versus prednisolone retention enemas in active distal ulcerative colitis.
Scand J Gastroenterol 1987; 22: 987-992.

Danielsson ┼, L÷fberg R, Persson T, Salde L, Schi÷ler R, Suhr O, WillÚn R.
A steroid enema, budesonide, lacking systemic effects for the treatment of distal ulcerative colitis or proctitis.
Scand J Gastroenterol 1992; 27: 9-12.

Johansson S┼, Andersson KE, Brattsand R, Gruvstad E, Hedner P.
Topical and systemic glucocorticoid potencies of budesonide, beclomethasone dipropionate and prednisolone in man.
Eur J Resp Dis 1982; 63 (22): 74-82.

L÷fberg R. et al.
Budesonide versus prednisolone enema in active distal ulcerative colitis. A comparative eight week study.
Gut 1993;34(Suppl 1):T162.

CLICK HERE FOR ENTOCORT CAPSULES PRODUCT MONOGRAPH

CLICK HERE FOR ABSTRACTS

CLICK HERE FOR LOSEC PI