Ortikos

Patient Information

ORTIKOS™
( or-TEE-kos )
(budesonide) extended-release capsules, for oral use

Read this Patient Information before you start taking ORTIKOS and each time you get a refill. There may benew information. This information does not take the place of talking to your healthcare provider about yourmedical condition or your treatment.

What is ORTIKOS?

ORTIKOS is a prescription corticosteroid medicine used to treat mild to moderate Crohn’s disease that affectspart of the small intestine (ileum) and part of the large intestine (ascending colon):

• in people 8 years of age and older with active Crohn’s disease
• in adults to help keep symptoms from coming back for up to 3 months

It is not known if ORTIKOS is safe and effective in children under 8 years of age, or in children 8 to 17 yearsof age who weigh 55 pounds (25 kg) or less, for the treatment of mild to moderate active Crohn’s disease thataffects part of the small intestine and part of the large intestine.

It is not known if ORTIKOS is safe and effective in children to help keep symptoms of mild to moderateCrohn’s disease that affects part of the small intestine and part of the large intestine from coming back.

Do not take ORTIKOS if:

• you are allergic to budesonide or any of the ingredients in ORTIKOS. See the end of this leaflet for acomplete list of ingredients in ORTIKOS.

Before you take ORTIKOS tell your healthcare provider if you have any other medical conditionsincluding if you:

• have liver problems.
• are planning to have surgery.
• have chicken pox or measles or have recently been near anyone with chicken pox or measles.
• have an infection.
• have diabetes or glaucoma or have a family history of diabetes or glaucoma.
• have cataracts.
• have or had tuberculosis.
• have high blood pressure (hypertension).
• have decreased bone mineral density (osteoporosis).
• have stomach ulcers.
• are pregnant or plan to become pregnant. ORTIKOS may harm your unborn baby. Talk to your healthcareprovider about the possible risk to your unborn baby if you take ORTIKOS when you are pregnant. Tellyour healthcare provider right away if you become pregnant or think you may be pregnant during yourtreatment with ORTIKOS.
• are breastfeeding or plan to breastfeed. It is not known if ORTIKOS passes into your breast milk or if it willaffect your baby. Talk to your healthcare provider about the best way to feed your baby if you takeORTIKOS.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-countermedicines, vitamins, and herbal supplements. ORTIKOS and other medicines may affect each other causingside effects.

How should I take ORTIKOS?

• Take ORTIKOS exactly as your healthcare provider tells you.
• Your healthcare provider will tell you how many ORTIKOS capsules to take. Your healthcare provider maychange your dose if needed.
• Take ORTIKOS 1 time each day in the morning.
• Take ORTIKOS capsules whole. Do not chew or crush ORTIKOS capsules before swallowing. If you take too many ORTIKOS capsules call your healthcare provider right away or go to the nearesthospital emergency room.

What should I avoid while taking ORTIKOS?

• Do not drink grapefruit juice during your treatment with ORTIKOS. Drinking grapefruit juice can increasethe level of ORTIKOS in your blood.

What are the possible side effects of ORTIKOS?

ORTIKOS may cause serious side effects, including:

• Effects of having too much corticosteroid medicine in your blood (hypercorticism). Long-time use ofORTIKOS can cause you to have too much corticosteroid medicine in your blood. Tell your healthcareprovider if you have any of the following signs and symptoms of hypercorticism:
  • acne
  • bruise easily
  • rounding of your face (moon face)
  • ankle swelling
  • thicker or more hair on your body and face
  • a fatty pad or hump between your shoulders(buffalo hump)
  • pink or purple stretch marks on the skin or yourabdomen, thighs, breasts and arms
• Adrenal suppression. When ORTIKOS is taken for a long period of time (chronic use), kidney (adrenal)suppression can happen. This is a condition in which the adrenal glands do not make enough steroidhormones. Symptoms of adrenal suppression include: tiredness, weakness, nausea and vomiting and lowblood pressure. Tell your healthcare provider if you are under stress or have any symptoms of adrenalsuppression during treatment with ORTIKOS.
• Worsening of allergies.If you take certain other corticosteroid medicines to treat allergies, switching toORTIKOS may cause your allergies to come back. These allergies may include a skin condition calledeczema or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergiesbecome worse while taking ORTIKOS. Increased risk of infection.
• ORTIKOS weaken your immune system. Taking medicines that weaken yourimmune system makes you more likely to get infections. Avoid contact with people who have contagiousdiseases, such as chicken pox or measles, while taking ORTIKOS. Tell your healthcare provider right awayif you come in contact with anyone who has chicken pox or measles.
• Tell your healthcare provider about any signs or symptoms of infection during treatment with ORTIKOS,including:
  • fever
  • chills
  • pain
  • feeling tired
  • aches
  • nausea and vomiting

The most common side effects of ORTIKOS in adults include:

• • headache
  • infection in your air passages (respiratoryinfection)
  • nausea
  • back pain

• indigestion
• dizziness
• stomach area (abdominal) pain
• gas
• vomiting
• tiredness
• pain

The most common side effects of ORTIKOS in children 8 to 17 years of age, who weigh more than 55pounds (25 kg), are similar to the most common side effects in adults.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of ORTIKOS. For more information, ask your healthcare provider orpharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ORTIKOS?

• Store ORTIKOS at room temperature between 68° to 77°F (20° to 25°C).
• Keep ORTIKOS in a tightly closed container.

Keep ORTIKOS and all medicines out of reach of children.

General information about the safe and effective use of ORTIKOS.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do notuse ORTIKOS for a condition for which it was not prescribed. Do not give ORTIKOS to other people, even ifthey have the same symptoms that you have. It may harm them. You can ask your healthcare provider orpharmacist for information about ORTIKOS that is written for health professionals.

What are the ingredients in ORTIKOS?

Active ingredient: budesonide

Inactive ingredients: acetyl tributyl citrate, corn starch, ethylcellulose aqueous dispersion, methacrylic acidand ethyl acrylate copolymer dispersion, polysorbate 80, simethicone emulsion, sucrose, talc, and triethylcitrate.

Capsule shell contains gelatin, iron oxide black (for 6 mg), iron oxide red, iron oxide yellow, sodium laurylsulphate and titanium dioxide.

The imprinting ink contains, black iron oxide, potassium hydroxide and shellac.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Description

Budesonide, the active ingredient in ORTIKOS, is a synthetic corticosteroid. Budesonide is designated chemically as (RS)-11β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The molecular formula of budesonide is C₂₅H₃₄O₆ and its molecular weight is 430.5. Its structural formula is:

 

 

Budesonide is a white to off-white powder that is practically insoluble in water and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 5 is 1.6 x 10³ ionic strength 0.01.

Each extended-release capsule for oral administration contains 6 mg and 9 mg of budesonide, USP (micronized) with the following inactive ingredients: acetyl tributyl citrate, corn starch, ethylcellulose aqueous dispersion, methacrylic acid and ethyl acrylate copolymer dispersion, polysorbate 80, simethicone emulsion, sucrose, talc, and triethyl citrate.

Capsule shell contains gelatin, iron oxide black (for 6 mg), iron oxide red, iron oxide yellow, sodium lauryl sulphate and titanium dioxide.

The imprinting ink contains black iron oxide, potassium hydroxide and shellac.

Indications

Treatment Of Mild To Moderate Active Crohn’s Disease

ORTIKOS is indicated for the treatment of mild to moderate active Crohn’s disease involving the ileum and/orthe ascending colon in patients 8 years of age and older.

Maintenance Of Clinical Remission Of Mild To Moderate Crohn’s Disease

ORTIKOS is indicated for the maintenance of clinical remission of mild to moderate Crohn’s disease involvingthe ileum and/or the ascending colon for up to 3 months in adults.

Dosage And Administration

Administration Instructions

• Take ORTIKOS once daily in the morning.
• Swallow ORTIKOS whole. Do not chew or crush.
• Avoid consumption of grapefruit juice for the duration of therapy with ORTIKOS [see DRUG INTERACTIONS].

Treatment Of Mild To Moderate Active Crohn’s Disease

The recommended dosage of ORTIKOS is:

Adults

9 mg orally once daily for up to 8 weeks. Repeated 8 week courses of ORTIKOS can be given forrecurring episodes of active disease.

Pediatric Patients 8 To 17 Years Who Weigh More Than 25 kg

9 mg orally once daily for up to 8 weeks, followedby 6 mg once daily for 2 weeks.

Maintenance Of Clinical Remission Of Mild To Moderate Crohn’s Disease

The recommended dosage in adults, following an 8 week course(s) of treatment for active disease and once thepatient’s symptoms are controlled (CDAI less than 150), is ORTIKOS 6 mg orally once daily for maintenance ofclinical remission up to 3 months. If symptom control is still maintained at 3 months an attempt to taper tocomplete cessation is recommended. Continued treatment with ORTIKOS 6 mg for more than 3 months has notbeen shown to provide substantial clinical benefit.

Patients with mild to moderate active Crohn’s disease involving the ileum and/or ascending colon have beenswitched from oral prednisolone to ORTIKOS with no reported episodes of adrenal insufficiency. Sinceprednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating ORTIKOStreatment.

How Supplied

Dosage Forms And Strengths

Extended-Release Capsules:

• 6 mg: hard gelatin capsules with light grey colored cap and pink colored body imprinted with “061” on capand body in black ink containing white to off-white pellets.
• 9 mg: hard gelatin capsules with pink colored cap and pink colored body imprinted with “062” on cap andbody in black ink containing white to off-white pellets.

Storage And Handling

• ORTIKOS 6 mg are hard gelatin capsules with light grey colored cap and pink colored body imprinted with”061″ on cap and body in black ink containing white to off-white pellets.

Bottles of 30’s with Child Resistant Cap – NDC 55566-1002-1

• ORTIKOS 9 mg are hard gelatin capsules with pink colored cap and pink colored body imprinted with”062″ on cap and body in black ink containing white to off-white pellets.

Bottles of 30’s with Child Resistant Cap – NDC 55566-1020-1

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP ControlledRoom Temperature].

Keep container tightly closed.

Manufactured by: Sun Pharmaceutical Industries Ltd. Halol-Baroda Highway, Halol-389 350, Gujarat, India. Revised: Oct 2019.

The following clinically significant adverse reactions are described elsewhere in labeling:

• Hypercorticism and adrenal axis suppression [see WARNINGS AND PRECAUTIONS]
• Symptoms of steroid withdrawal in those patients transferred from other systemic corticosteroids [see WARNINGS AND PRECAUTIONS]
• Increased risk of infection [see WARNINGS AND PRECAUTIONS]
• Other corticosteroid effects [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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

The safety of ORTIKOS has been established from adequate and well-controlled studies of another oralbudesonide product [see Clinical Studies]. Below is a display of the adverse reactions of budesonide inthese adequate and well-controlled studies.

Adults

The data described below reflect exposure to budesonide in 520 patients with Crohn’s disease, including 520exposed to 9 mg per day (total daily dose) for 8 weeks and 145 exposed to 6 mg per day for one year in placebocontrolled clinical trials. Of the 520 patients, 38% were males and the age range was 17 to 74 years.

Treatment of Mild to Moderate Active Crohn’s Disease

The safety of budesonide was evaluated in 651 adult patients in five clinical trials of 8 weeks duration inpatients with active mild to moderate Crohn’s disease. The most common adverse reactions, occurring in greaterthan or equal to 5% of the patients, are listed in Table 1.

Table 1: Common Adverse Reactions* in 8-Week Treatment Clinical Trials

Adverse Reaction	Budesonide 9 mg n=520	Placebo n=107	Prednisolone† 40 mg n=145	Comparator‡ n=88
	Number (%)	Number (%)	Number (%)	Number (%)
Headache	107(21)	19(18)	31(21)	11(13)
RespiratoryInfection	11(13)	7(7)	20(14)	5(6)
Nausea	57(11)	10(9)	18(12)	7(8)
Back Pain	36(7)	10(9)	17(12)	5(6)
Dyspepsia	31(6)	4(4)	17(12)	3(3)
Dizziness	38(7)	5(5)	18(12)	5(6)
Abdominal Pain	32(6)	18(17)	6(4)	10(11)
Flatulence	30(6)	6(6)	12(8)	5(6)
Vomiting	29(6)	6(6)	6(4)	6(7)
Fatigue	25(5)	8(7)	11(8)	0(0)
Pain	24(5)	8(7)	17(12)	2(2)
* Occurring in greater than or equal to 5% of the patients in any treated group. † Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mgper week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mgper week. ‡ This drug is not approved for the treatment of Crohn’s disease in the United States.

 

The incidence of signs and symptoms of hypercorticism reported by active questioning of patients in 4 of the 5short-term clinical trials are displayed in Table 2.

Table 2: Summary and Incidence of Signs/Symptoms of Hypercorticism in 8-Week Treatment Clinical Trials

Signs/Symptom	Budesonide 9 mg n=427	Placebo n=107	Prednisolone* 40mg n=145
	Number (%)	Number (%)	Number (%)
Total	145 (34%)	29 (27%)	69 (48%)
Acne	63(15)	14(13)	33(23)†
Bruising Easily	63(15)	12(11)	13(9)
Moon Face	46(11)	4(4)	53(37)†
Swollen Ankles	32(7)	6(6)	13(9)
Hirsutism	22(5)	2(2)	5(3)
Buffalo Hump	6(1)	2(2)	5(3)
Skin Striae	4(1)	2(2)	0
* Prednisolone tapering scheme: either 40 mg in week 1-2, thereafter tapering with 5mg/week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5mg/week. † Statistically significantly different from budesonide 9 mg ‡ Including hair growth increased, local and hair growth increased, general

 

Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease

The safety of budesonide was evaluated in 233 adult patients in four long-term clinical trials (52 weeks) ofmaintenance of clinical remission in patients with mild to moderate Crohn’s disease. A total of 145 patientswere treated with budesonide 6 mg once daily.

The adverse reaction profile of budesonide 6 mg once daily in maintenance of Crohn’s disease was similar tothat of short-term treatment with budesonide 9 mg once daily in active Crohn’s disease. In the long-term clinicaltrials, the following adverse reactions occurred in greater than or equal to 5% and are not listed in Table 1:diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%).

Signs/symptoms of hypercorticism reported by active questioning of patients in the long-term maintenanceclinical trials are displayed in Table 3.

Table 3: Summary and Incidence of Signs/Symptoms of Hypercorticism inLong-Term Clinical Trials

Signs/Symptom	Budesonide 6 mg n=145	Placebo n=143
	Number (%)	Number (%)
Bruising Easily	15(10)	5(4)
Acne	14(10)	3(2)
Moon Face	6(4)	0
Hirsutism	5(3)	1(1)
Swollen Ankles	3(2)	3(2)
Buffalo Hump	1(1)	0
Skin Striae	0	0

 

The incidence of signs/symptoms of hypercorticism as described above in long-term maintenance clinical trialswas similar to that seen in the short-term treatment clinical trials.

Less Common Adverse Reactions in Treatment and Maintenance Clinical Trials

Less common adverse reactions (less than 5%), occurring in adult patients treated with budesonide 9 mg (totaldaily dose) in short-term treatment clinical studies and/or budesonide 6 mg (total daily dose) in long-termmaintenance clinical trials, with an incidence are listed below by system organ class:

Cardiac disorders: palpitation, tachycardia

Eye disorders: eye abnormality, vision abnormal

General disorders and administration site conditions: asthenia, chest pain, dependent edema, face edema, flu-like disorder, malaise, fever

Gastrointestinal disorders: anus disorder, enteritis, epigastric pain, gastrointestinal fistula, glossitis,hemorrhoids, intestinal obstruction, tongue edema, tooth disorder

Infections and infestations: Ear infection -not otherwise specified, bronchitis, abscess, rhinitis, urinary tractinfection, thrush

Investigations: weight increased

Metabolism and nutrition disorders: appetite increased

Musculoskeletal and connective tissue disorders: arthritis, cramps, myalgia

Nervous system disorders: hyperkinesia, paresthesia, tremor, vertigo, somnolence, amnesia

Psychiatric disorders: agitation, confusion, insomnia, nervousness, sleep disorder

Renal and urinary disorders: dysuria, micturition frequency, nocturia

Reproductive system and breast disorders: intermenstrual bleeding, menstrual disorder

Respiratory, thoracic and mediastinal disorders: dyspnea, pharynx disorder

Skin and subcutaneous tissue disorders: alopecia, dermatitis, eczema, skin disorder, sweating increased, purpura

Vascular disorders: flushing, hypertension

Bone Mineral Density

A randomized, open, parallel-group multicenter safety clinical trial specifically compared the effect ofbudesonide (less than 9 mg per day) and prednisolone (less than 40 mg per day) on bone mineral density over 2years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less withbudesonide than with prednisolone in steroid-naïve patients, whereas no difference could be detected betweentreatment groups for steroid-dependent patients and previous steroid users. The incidence of symptomsassociated with hypercorticism was significantly higher with prednisolone treatment.

Clinical Laboratory Test Findings

The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationshipto budesonide, were reported in greater than or equal to 1% of patients: hypokalemia, leukocytosis, anemia,hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypicalneutrophils, c-reactive protein increased and adrenal insufficiency.

Pediatric Patients –Treatment of Mild to Moderate Active Crohn’s Disease

Adverse reactions reported in pediatric patients 8 to 17 years of age, who weigh more than 25 kg, were similarto those reactions described above in adult patients.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of another oral formulation ofbudesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Anaphylactic reactions

Nervous System Disorders: Benign intracranial hypertension

Psychiatric Disorders: Mood swings

Drug Interactions

CYP3A4 Inhibitors

Budesonide is a substrate for CYP3A4. Avoid use with CYP3A4 inhibitors. Concomitant oral administration ofa strong CYP3A4 inhibitor (ketoconazole) caused an eight-fold increase of the systemic exposure to oralbudesonide. Inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir, indinavir, saquinavir,erythromycin, and cyclosporine) can increase systemic budesonide concentrations [see CLINICAL PHARMACOLOGY].

Grapefruit Juice

Avoid ingestion of grapefruit juice with ORTIKOS. Intake of grapefruit juice which inhibitsCYP3A4 activity can increase the systemic exposure to budesonide [see CLINICAL PHARMACOLOGY] .

Included as part of the “PRECAUTIONS” Section

Precautions

Hypercorticism And Adrenal Axis Suppression

When corticosteroids are used chronically, systemic effects such as hypercorticism and adrenal axis suppressionmay occur. Corticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress.In situations where patients are subject to surgery or other stress situations, supplementation with a systemiccorticosteroid is recommended. Since ORTIKOS contains a corticosteroid, general warnings concerningcorticosteroids should be followed [see Symptoms Of Steroid Withdrawal In Patients Transferred From Other Systemic Corticosteroids, Increased Risk Of Infection, Other Corticosteroid Effects].

Pediatric patients with Crohn’s disease have a slightly higher systemic exposure of budesonide and increasedcortisol suppression than adults with Crohn’s disease [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C respectively) could be at anincreased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oralbudesonide. Avoid use of ORTIKOS in patients with moderate and severe hepatic impairment. [see Use In Specific Populations].

Symptoms Of Steroid Withdrawal In Patients Transferred From Other Systemic Corticosteroids

Monitor patients who are transferred from corticosteroid treatment with high systemic effects to corticosteroidswith lower systemic availability, such as budesonide, since symptoms attributed to withdrawal of steroidtherapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop.Adrenocortical function monitoring may be required in these patients and the dose of corticosteroid treatmentwith high systemic effects should be reduced cautiously.

Replacement of systemic corticosteroids with budesonide may unmask allergies (e.g., rhinitis and eczema),which were previously controlled by the systemic drug.

Increased Risk Of Infection

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthyindividuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptiblepatients or patients on immunosuppressant doses of corticosteroids. In patients who have not had these diseases,particular care should be taken to avoid exposure.

How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminatedinfection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to therisk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenousimmunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooledintramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG). Ifchicken pox develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection,untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.

Other Corticosteroid Effects

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or witha family history of diabetes or glaucoma, or with any other condition where corticosteroids may have unwantedeffects.

Patient Counseling Information

Advise Patients to read the FDA-Approved patient labeling (PATIENT INFORMATION).

Hypercorticism And Adrenal Axis Suppression

Advise patients that ORTIKOS may cause hypercorticism and adrenal axis suppression and to follow a taperschedule, as instructed by their healthcare provider if transferring to ORTIKOS from systemic corticosteroids [see WARNINGS AND PRECAUTIONS ,] . Advise patients that replacement of systemic corticosteroids withORTIKOS may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemicdrug.

Increased Risk Of Infection

Advise patients to avoid exposure to people with chicken pox or measles and, if exposed, to consult theirhealthcare provider immediately. Inform patients that they are at increased risk of developing a variety ofinfections; including worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections or ocularherpes simplex and to contact their healthcare provider if they develop any symptoms of infection [see WARNINGS AND PRECAUTIONS] .

Pregnancy

Advise female patients that ORTIKOS may cause fetal harm and to inform their healthcare provider with aknown or suspected pregnancy [see Use In Specific Populations].

Administration

Advise patients to:

• Take ORTIKOS once daily in the morning.
• Swallow ORTIKOS capsules whole. Do not chew or crush.
• Avoid consumption of grapefruit juice for the duration of therapy with ORTIKOS [see DRUG INTERACTIONS] .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at anoral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surfacearea basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) andabove. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times themaximum recommended human dose on a body surface area basis). In an additional two-year study in maleSprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times themaximum recommended human dose on a body surface area basis). However, it caused a statistically significantincrease in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times themaximum recommended human dose on a body surface area basis). The concurrent reference corticosteroids(prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonidecaused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times themaximum recommended human dose on a body surface area basis).

Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK ) test,the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethalitytest, the rat hepatocyte UDS test and the mouse micronucleus test.

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 timesthe maximum recommended human dose on a body surface area basis). However, it caused a decrease inprenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommendedhuman dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately0.005 times the maximum recommended human dose on a body surface area basis).

Use In Specific Populations

Pregnancy

Risk Summary

Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficientto inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical Considerations). In animal reproduction studies with pregnant rats and rabbits, administration ofsubcutaneous budesonide during organogenesis at doses approximately 0.5 times or 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletalabnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels [ see Data]. Based onanimal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage of the indicated population is unknown.All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. generalpopulation, the estimated background risk of major birth defects and miscarriage in clinically recognizedpregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Some published epidemiological studies show an association of adverse pregnancy outcomes in women withCrohn’s disease, including preterm birth and low birth weight infants, during periods of increased diseaseactivity (including increased stool frequency and abdominal pain). Pregnant women with Crohn’s disease shouldbe counseled regarding the importance of controlling disease.

Fetal/Neonatal adverse reactions

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infantsshould be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, andvomiting, and managed accordingly [see WARNINGS AND PRECAUTIONS].

Data

Animal Data

Budesonide was teratogenic and embryolethal in rabbits and rats.

In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the periodof organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneousdoses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended humandose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during theperiod of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects onfetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg inrabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis).Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg inrabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface areabasis).

In a peri- and post-natal development study, rats dosed subcutaneously with budesonide during the period ofDay 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect ongrowth and development of offspring. In addition, offspring survival was reduced and surviving offspring haddecreased mean body weights at birth and during lactation at exposures 0.02 times the MRHD (on a mg/m basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence ofmaternal toxicity.

Lactation

Risk Summary

Lactation studies have not been conducted with oral budesonide, including ORTIKOS, and no information isavailable on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Onepublished study reports that budesonide is present in human milk following maternal inhalation of budesonide(see Data). The developmental and health benefits of breastfeeding should be considered along with themother’s clinical need for ORTIKOS and any potential adverse effects on the breastfed infant from ORTIKOS,or from the underlying maternal condition.

Data

One published study reports that budesonide is present in human milk following maternal inhalation ofbudesonide which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosageand a milk/plasma ratio ranging between 0.4 and 0.5. Budesonide plasma concentrations were not detected andno adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. Therecommended daily dose of ORTIKOS is higher (up to 9 mg daily) compared with inhaled budesonide (up to800 mcg daily) given to mothers in the above described study. The maximum budesonide plasma concentrationfollowing a 9 mg daily dose (in both single-and repeated-dose pharmacokinetic studies) of oral budesonide isapproximately 5 nmol/L to 10 nmol/L which is up to 10 times higher than the 1 nmol/L to 2 nmol/L for a 800mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Assuming the coefficient ofextrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses ofORTIKOS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonideinhalation.

Pediatric Use

The safety and effectiveness of ORTIKOS have been established in pediatric patients 8 to 17 years of age whoweigh more than 25 kg for the treatment of mild to moderate active Crohn’s disease involving the ileum and/orthe ascending colon. Use of ORTIKOS in this age group is supported by evidence from adequate and wellcontrolled studies of oral budesonide in adults, with additional data from 2 clinical studies in 149 pediatricpatients treated up to 8 weeks and one pharmacokinetic study in 8 pediatric patients [see ADVERSE REACTIONS , CLINICAL PHARMACOLOGY and Clinical Studies] .

The observed safety profile of oral budesonide in pediatric patients is consistent with its known safety profile inadults and no new safety concerns were identified [see ADVERSE REACTIONS ] .

The safety and effectiveness of ORTIKOS have not been established in pediatric patients less than 8 years ofage for the treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon. The safety and effectiveness of ORTIKOS have not been established in pediatric patients for the maintenance ofclinical remission of mild to moderate Crohn’s disease. An open-label study to evaluate the safety andtolerability of oral budesonide as maintenance treatment in pediatric patients aged 5 to 17 years was conducted,and did not establish the safety and efficacy of maintenance of clinical remission.

Systemic corticosteroids, including ORTIKOS, may cause a reduction of growth velocity in pediatric patients.Pediatric patients with Crohn’s disease have a 17% higher mean systemic exposure and cortisol suppressionthan adults with Crohn’s disease [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Geriatric Use

Clinical studies of oral budesonide did not include sufficient numbers of patients aged 65 and over to determinewhether they respond differently from younger patients. Of the 651 patients treated with oral budesonide inclinical studies, 17 (3%) were greater than or equal to 65 years of age and none were greater than 74 years ofage. Other reported clinical experience has not identified differences in responses between the elderly andyounger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the lowend of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and ofconcomitant disease or other drug therapy.

Hepatic Impairment

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C, respectively) could be at anincreased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure tobudesonide [see WARNINGS AND PRECAUTIONS] . Avoid use of ORTIKOS in patients with moderate and severehepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment (Child-PughClass A).

Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. Treatment consists ofimmediate gastric lavage or emesis followed by supportive and symptomatic therapy.

If corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such ashypercorticism and adrenal axis suppression may occur. For chronic overdosage in the case of severe diseaserequiring continuous steroid therapy, the dosage may be reduced temporarily.

Single oral doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acutetoxicity were decreased motor activity, piloerection and generalized edema.

Contraindications

ORTIKOS is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of thecapsules. Serious hypersensitivity reactions, including anaphylaxis have occurred [see ADVERSE REACTIONS].

Mechanism Of Action

Budesonide is an anti-inflammatory corticosteroid and has a high glucocorticoid effect and a weakmineralocorticoid effect, and the affinity of budesonide to glucocorticoid receptors, which reflects the intrinsicpotency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone.

Pharmacodynamics

Treatment with glucocorticoids, including ORTIKOS is associated with a suppression of endogenous cortisolconcentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. There was apositive correlation between the percent (%) reduction of AUC0-24 of plasma cortisol and systemic exposure tobudesonide both in pediatric and adult patients.

Adults

Plasma cortisol suppression was compared following five days’ administration of oral budesonide andprednisolone in a crossover study in healthy volunteers. The mean decrease in the area under the plasma cortisolconcentration-time curve over 24 hour (AUC0-24 ) was greater (78%) with prednisolone 20 mg per daycompared to 45% with budesonide 9 mg per day.

Pediatric Patients

The effect of budesonide on endogenous cortisol concentrations was compared between pediatric patients (n=8,aged 9 to 14 years) and adults (n=6) with active Crohn’s disease following administration of oral budesonide 9mg once daily for 7 days. Compared to baseline values before treatment, the mean decrease in the AUC ofcortisol was 64% (±18%) in pediatric patients and 50% (±27%) in adults after budesonide treatment [see WARNINGS AND PRECAUTIONS , ADVERSE REACTIONS and Use In Specific Populations].

The responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) was studied in pediatric patientsaged 8 to 17 years, with mild to moderate active Crohn’s disease in randomized, double-blind, active controlstudy [see Clinical Studies] . After 8 weeks of treatment with oral budesonide 9 mg once daily or withprednisolone, administered at tapering doses starting from 1 mg/kg, the proportion of patients with normalresponse to the ACTH challenge was 6% in the budesonide group compared to none in the prednisolone group;the proportion of patients with morning p-cortisol of greater than 5 mcg/dL was 50% in the budesonide groupcompared to 22% in the prednisolone group. The mean morning p-cortisol was 6.3 mcg/dL in the budesonidegroup and 2.6 mcg/dL in the prednisolone group (Table 4).

Table 4: Proportion of Pediatric Patients 8 to 17 years old with PeakEndogenous Cortisol Levels (above 18 mcg/dL) after ACTH Stimulation andNormal Response to ACTH Challenge Following Administration of OralBudesonide or Prednisolone for 8 weeks

	Budesonide	Prednisolone
Peak plasma cortisol above 18 mcg/dL
At baseline	91% (20/22)	91% (21/23)
At week 8	25% (4/16)	0% (0/18)
Normal response* to ACTH challenge
At baseline	73% (16/22)	78% (18/23)
At week 8	6% (1/16)	0% (0/18)
* The normal response to ACTH challenge included 3 criteria, as defined in the cosyntropinlabel: 1) morning cortisol level above 5 mcg/dL; 2) increase in cortisol level by at least 7mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisollevel of above 18 mcg/dL following ACTH challenge. Cortisol concentration wasmeasured at 30 min after intravenous or intramuscular injection of 0.25 mg cosyntropin atbaseline and at week 8 after treatment.

 

Pharmacokinetics

Absorption

Following administration of oral budesonide, the time to peak concentration varied in individual patientsbetween 2.5 to 8 hours. Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and inhealthy subjects, demonstrating a high first-pass elimination of the drug.

Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3mg to 15 mg. No accumulation of budesonide was observed following repeated dosing.

Following administration of oral budesonide 9 mg for five days in healthy subjects, the mean peak plasmaconcentration and the steady state area under the plasma concentration time curve for budesonide were 5.3 ± 1.8nmol/L and 37.0 ±14.6 nmol·hr/L, respectively.

Following administration of oral budesonide 9 mg once daily in patients with active Crohn’s disease, the meanpeak plasma concentration and AUC were 4.0 ±2.1 nmol/L and 35.0 ±19.8 nmol·h/L, respectively.

Concomitant administration of a high-fat meal delayed the time to peak concentration of budesonide by 1 hourand overall exposure was increased by about 25%.

Distribution

The mean volume of distribution (Vss) of budesonide varied between 2.2 L/kg and 3.9 L/kg in healthy subjectsand in patients. Plasma protein binding was estimated to be 85% to 90% in the concentration range 1 nmol/L to230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrationswas about 0.8.

Elimination

Budesonide had a plasma clearance, 0.9 L/min to 1.8 L/min in healthy adults. Mean plasma clearance afterintravenous administration of budesonide in patients with Crohn’s disease was 1.0 L/min. These plasmaclearance values approached the estimated liver blood flow, and, accordingly, suggest that budesonide is a highhepatic clearance drug. The plasma elimination half-life, after administration of intravenous doses rangedbetween 2 and 3.6 hours, and did not differ between healthy adults and patients with Crohn’s disease.

Metabolism

Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments inhuman liver microsomes demonstrated that budesonide is rapidly and extensively biotransformed, mainly byCYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The corticosteroidactivity of these metabolites was negligible (less than 1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects were in agreement with the in vitro findings.

Excretion

Budesonide was excreted in urine and feces in the form of metabolites. After oral as well as intravenousadministration of micronized [³H]-budesonide, approximately 60% of the recovered radioactivity was found inurine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainlyrenally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine.

Specific Populations

Age: Pediatric Population (8 Years And Older)

The pharmacokinetics of budesonide were investigated in pediatric patients aged 9 to 14 years (n=8) after oraladministration of budesonide and intravenous administration of budesonide. Following administration of 9 mgoral budesonide once daily for 7 days, the median time to peak plasma concentration of budesonide was 5 hoursand the mean peak plasma concentration was 6.0 ± 3.5 nmol/L. The mean AUC was 41.3 ±12.2 nmol·h/L and17% higher than that in adult patients with Crohn’s disease in the same study. The mean absolute oralavailability was 9.2% (3 to 17%; n=4) in pediatric patients.

After single dose administration of intravenous budesonide (n=4), the mean volume of distribution (V ) was2.2 ± 0.4 L/kg and mean clearance was 0.81 ± 0.2 L/min. The mean elimination half-life was 1.9 hours in 3 ss pediatric patients. The body-weight normalized clearance in pediatric patients was 20.5 mL/min/kg incomparison to 15.9 mL/min/kg in adult patients after intravenous administration [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Patients With Hepatic Impairment

In patients with mild (Child-Pugh Class A, n=4) or moderate (Child-Pugh Class B, n=4) hepatic impairment,budesonide 4 mg was administered orally as a single dose. The patients with moderate hepatic impairment had a3.5-fold higher AUC compared to the healthy subjects with normal hepatic function while the patients with mildhepatic impairment had an approximately 1.4-fold higher AUC. The Cmax values demonstrated similarincreases [see WARNINGS AND PRECAUTIONS] . The increased systemic exposure in patients with mild hepaticimpairment was not considered to be clinically relevant. Patients with severe liver impairment (Child-PughClass C) were not studied [see Use In Specific Populations] .

Drug Interaction Studies

Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrationsof budesonide several-fold. Conversely, induction of CYP3A4 potentially could result in the lowering ofbudesonide plasma concentrations.

Effects Of Other Drugs On Budesonide

Ketoconazole

In an open, non-randomized, cross-over study, 6 healthy subjects were given budesonide 10 mg as a single dose,either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mgtwice daily. Coadministration of ketoconazole resulted in an eight-fold increase in AUC of budesonide,compared to budesonide alone [see DRUG INTERACTIONS] .

Grapefruit Juice

In an open, randomized, cross-over study, 8 healthy subjects were given oral budesonide 3 mg, either alone, orconcomitantly with 600 mL concentrated grapefruit juice (which inhibits CYP3A4 activity predominantly in theintestinal mucosa), on the last of 4 daily administrations. Concomitant administration of grapefruit juice resultedin a 2-fold increase of the bioavailability of budesonide compared to budesonide alone [see DRUG INTERACTIONS] .

Oral Contraceptives (CYP3A4 Substrates)

In a parallel study, the pharmacokinetics of budesonide were not significantly different between healthy femalesubjects who received oral contraceptives containing desogestrel 0.15 mg and ethinyl estradiol 30 mcg andhealthy female subjects who did not receive oral contraceptives. Budesonide 4.5 mg once daily (one-half therecommended dose) for one week did not affect the plasma concentrations of ethinyl estradiol, a CYP3A4substrate. The effect of budesonide 9 mg once daily on the plasma concentrations of ethinyl estradiol was notstudied.

Omeprazole

In a study in 11 healthy subjects, performed in a double-blind, randomized, placebo controlled manner, theeffect of 5 to 6 days treatment with omeprazole 20 mg once daily on the pharmacokinetics of budesonideadministered as oral budesonide 9 mg as a single dose was investigated. Omeprazole 20 mg once daily did notaffect the absorption or pharmacokinetics of budesonide.

Cimetidine

In an open, non-randomized, cross-over study, the potential effect of cimetidine on the pharmacokinetics ofbudesonide was studied. Six healthy subjects received cimetidine 1 gram daily (200 mg with meals and 400 mgat night) for 2 separate 3-day periods. Budesonide 4 mg was administered either alone or on the last day of oneof the cimetidine treatment periods. Coadministration of cimetidine resulted in a 52% and 31% increase in thebudesonide peak plasma concentration and the AUC of budesonide, respectively.

Clinical Studies

The safety and efficacy of ORTIKOS have been established based on adequate and well-controlled adult studiesof another oral budesonide product in patients with Crohn’s Disease. Below is a display of the results of theseadequate and well-controlled studies of budesonide in these conditions.

Treatment Of Mild To Moderate Active Crohn’s Disease

Adults

The efficacy of oral budesonide were evaluated in 994 patients with mild to moderate active Crohn’s disease ofthe ileum and/or ascending colon in 5 randomized and double-blind studies of 8 weeks duration. The studypatients ranged in age from 17 to 85 (mean 35), 40% were male and 97% were white. The Crohn’s DiseaseActivity Index (CDAI) was the main clinical assessment used for determining efficacy in these 5 studies.¹ TheCDAI is a validated index based on subjective aspects rated by the patient (frequency of liquid or very softstools, abdominal pain rating and general well-being) and objective observations (number of extraintestinalsymptoms, need for antidiarrheal drugs, presence of abdominal mass, body weight and hematocrit). Clinicalimprovement, defined as a CDAI score of less than or equal to 150 assessed after 8 weeks of treatment, was theprimary efficacy variable in these 5 comparative efficacy studies of oral budesonide. Safety assessments inthese studies included monitoring of adverse reactions. A checklist of potential symptoms of hypercorticismwas used.

One study (Study 1) compared the efficacy of budesonide 9 mg daily in the morning to a comparator. Atbaseline, the median CDAI was 272. Budesonide 9 mg daily resulted in a significantly higher clinicalimprovement rate at Week 8 than the comparator. See Table 5 .

Table 5: Clinical Improvement Rates (CDAI less than or equal to 150) After 8weeks of Treatment

Clinical Study	Budesonide		Comparator*	Placebo	Prednisolone
	9 mg Daily	4.5 mg TwiceDaily
1	62/91 (69%)†		37/83 (45%)
2		31/61 (51%)‡		13/64 (20%)
3	38/79 (48%)	41/78 (53%)		13/40 (33%)
4	35/58 (60%)	25/60 (42%)			35/58 (60%)
5	45/86 (52%)				56/85 (65%)
* This drug is not approved for the treatment of Crohn’s disease in the United States. † p=0.0004 compared to comparator. ‡ p=0.001 compared to placebo.

 

Two placebo-controlled clinical trials (Studies 2 and 3) were conducted. Study 2 involved 258 patients andtested the effects of graded doses of budesonide (1.5 mg twice daily, 4.5 mg twice daily, or 7.5 mg twice daily)versus placebo. At baseline, the median CDAI was 290. The 1.5 mg twice daily arm (data not shown) could notbe differentiated from placebo. The 4.5 mg twice daily arm was statistically different from placebo (Table 5),while no additional benefit was seen when the daily budesonide dose was increased to 15 mg per day (data notshown). Study 3 was a 3-armed parallel group study. The groups were treated with budesonide 9 mg once daily,budesonide 4.5 mg twice daily and placebo for 8 weeks, followed by a 2-week double-blind taper phase. Themedian CDAI at baseline was 263. Neither 9 mg daily nor 4.5 mg twice daily budesonide dose levels werestatistically different from placebo (Table 5). The recommended dosage of budesonide for the treatment of mildto moderate active Crohn’s disease involving the ileum and/or the ascending colon in adults is 9 mg once dailyin the morning for up to 8 weeks [see DOSAGE AND ADMINISTRATION] .

Two clinical trials (Studies 4 and 5) compared oral budesonide with oral prednisolone (initial dose 40 mg perday). Study 4 was a 3-armed parallel group study. The groups were treated with budesonide 9 mg once daily,budesonide 4.5 mg twice daily and prednisolone 40 mg (tapered dose) for 8 weeks, followed by a 4-weekdouble blind taper phase. At baseline, the median CDAI was 277. Equal clinical improvement rates (60%) wereseen in the budesonide 9 mg daily and the prednisolone groups in Study 4. In Study 5, 13% fewer patients in thebudesonide group experienced clinical improvement than in the prednisolone group (no statistical difference)(Table 5).

The proportion of patients with normal plasma cortisol values (greater than 150 nmol/L) was significantlyhigher in the budesonide groups in both trials (60% to 66%) than in the prednisolone groups (26% to 28%) atWeek 8.

Pediatric Patients (8 To 17 Years Of Age)

The effectiveness of oral budesonide, in pediatric patients aged 8 to 17 years, who weigh more than 25 kg withmild to moderate active Crohn’s disease (defined as Crohn’s Disease Activity Index (CDAI) ≥ 200) involvingthe ileum and/or the ascending colon, was assessed in one randomized, double-blind, active control study. Thisstudy compared budesonide 9 mg once daily, with prednisolone, administered at tapering doses starting from 1mg/kg. Twenty-two (22) patients were treated with budesonide and 24 patients were treated with prednisolone.After 8 weeks of treatment, 55% (95% CI: 32%, 77%) of patients treated with budesonide reached the endpoint(CDAI ≤150), as compared to 68% (95% CI: 47%, 89%) of patients treated with prednisolone. The averagenumber of liquid or very soft stools per day (assessed over 7 days) decreased from 1.49 at baseline to 0.96 aftertreatment with budesonide and 2.00 at baseline to 0.52 after treatment with prednisolone. The average daily abdominal pain rating (where 0=none, 1=mild, 2=moderate, and 3=severe) decreased from 1.49 at baseline to0.54 after treatment with budesonide and 1.64 at baseline to 0.38 after 8 weeks of treatment with prednisolone.

Use of budesonide in this age group is supported by evidence from adequate and well-controlled studies ofbudesonide in adults, and by safety and pharmacokinetic studies performed in pediatric patients.

Maintenance Of Clinical Remission Of Mild To Moderate Crohn’s Disease

Adults

The efficacy of oral budesonide for maintenance of clinical remission were evaluated in four double-blind,placebo-controlled, 12-month trials in which 380 patients were randomized and treated once daily with 3 mg or6 mg budesonide or placebo. Patients ranged in age from 18 to 73 (mean 37) years. Sixty percent of the patientswere female and 99% were Caucasian. The mean CDAI at entry was 96. Among the four clinical trials,approximately 75% of the patients enrolled had exclusively ileal disease. Colonoscopy was not performedfollowing treatment. Budesonide 6 mg per day prolonged the time to relapse, defined as an increase in CDAI ofat least 60 units to a total score greater than 150 or withdrawal due to disease deterioration. The median time torelapse in the pooled population of the 4 studies was 154 days for patients taking placebo, and 268 days forpatients taking budesonide 6 mg per day. Budesonide 6 mg per day reduced the proportion of patients with lossof symptom control relative to placebo in the pooled population for the 4 studies at 3 months (28% versus 45%for placebo).

REFERENCES

1. Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn’s Disease Activity Index, NationalCooperative Crohn’s Disease Study. Gastroenterology 1976; 70(3): 439-444.