Budesonide

Budesonide belongs to the Corticosteroids Pharmacological class.

Budesonide is approved for the treatment of Chronic Obstructive Pulmonary Disease, Crohn’s Disease, Asthma, Ulcerative Colitis, Hay Fever and allergies

An average of about 9-21% of bioavailability was reported in healthy patients treated with oral Budesonide. About 80-90% Budesonide is rapidly metabolized through first-pass metabolism. The volume of distribution of Budesonide was found to be 2.2-3.9L/kg. 60% of Budesonide is excreted in the urine.

The common side effects associated with Budesonide are headache, nausea, vomiting, gastric pain , cough etc.

Budesonide is available in the form of Tablets, Suspension for nebulization, Turbuhaler, nasal spray

Budesonide is available in India, U.K., U.S., Canada, India ,E.U., China, Japan, Australia.

Budesonide belonging to the pharmacological class of Corticosteroid. Budesonide is said to be a potent anti-inflammatory agent Budesonide binds and activates glucocorticoid receptors in the effector cell such as bronchial cytoplasm that allows the translocation of this budesonide-GR complex in the bronchi nucleus. This binds to both HDCA2 and CBP (HAT). The budesonide-CBP (HAT) receptor complex prevents the production of inflammatory genes that might cause bronchoconstriction. Also, the budesonide-receptor complex activates the HDCA2 increasing the gene expression, which reduces the formation of cytokines (such as Interleukins and Tumor Necrosis Factor).

Budesonide also inhibits the activation of the eosinophils by increasing apoptosis and also suppresses the activation of the inflammatory cells such as mast cells, neutrophils, T-lymphocytes, etc. The overall inhibition of Interleukins and Tumor Necrosis Factor leads to reduced airway inflammation and hyperreactivity, causing inhibition of the bronchospasm, wheezing, and coughing.

Budesonide hence leads to the treatment of Chronic Obstructive Pulmonary Disease, Crohn’s Disease, Asthma, Ulcerative Colitis, Hay Fever and allergies

Budesonide onset of action is found to be 24 hrs. After the initial treatment, and the duration of action is around 1-2 weeks. Budesonide Cmax was found to be 1.8 microg/L, and Tmax was found to be 0.46 hours.

Budesonide is available in breath Tablets and inhaler.

Tablets: Swallowed with water or liquid.

Inhaler:

• Single ampule is broken from the strip, leaving the rest in the foil sachet
• The ampoule is shaken gently
• The ampule is twisted open by twisting off the top
• All the liquid is squeezed from the ampoule into the nebulizer cup. The top of the nebulizer cup is removed and disposed of the empty ampoule carefully
• One end of the cup is connected to the mouthpiece or face mask and the other end to the air pump The cup is gently shaken once more then turn on the nebulizer. The mist is breathed calmly and deeply using the mouthpiece or face mask
• Treatment is complete when no more mist comes out of the mouthpiece or face mask.

Turbuhaler:

• Load dose by holding inhaler in upright position and turn greenish-blue grip as far as it will go in one direction and then turn it as far as it will go in the other direction.
• Prior to first use, this procedure should be done twice; with subsequent dosing, perform this procedure once.
• Clicking sound means inhaler is loaded with dose and ready for use.
• Exhale fully. Do not exhale into mouthpiece of inhaler.
• Place mouthpiece between teeth and close lips over mouthpiece. Inhale deeply and forcefully.
• Do not exhale through inhaler. If the Turbuhaler is dropped, shaken, or breathed into after it is loaded, the dose will be lost and a new dose will need to be loaded.
• Clean outside of mouthpiece once weekly with a dry tissue.
• Avoid getting inhaler wet.
• Discard device after a 0 displays in the dose window

Flexihaler

• Hold the top of the device and bottom of the cap is twisted to open.
• Twist the bottom brown part one way and then another way until click sound is heard.
• The inhaler is held under the chin and air is breathed out
• Now lips are tightly held around the mouthpiece and breathed in quickly.
• Hold the breathe around two seconds and put back the cap on the inhaler
• Rinse the mouth with water and spit it out.

Budesonide can be used in the treatment of:

• COPD (Chronic Obstructive Pulmonary Disease)
• Crohn’s Disease
• Asthma
• Ulcerative Colitis
• Hay fever
• Allergies

Budesonide can help to relieve symptoms of Chronic Obstructive Pulmonary Disease, Crohn’s Disease, Asthma, Ulcerative Colitis, Hay Fever and allergies.

Budesonide is approved for use in the following clinical indications:

• COPD (Chronic Obstructive Pulmonary Disease)
• Crohn’s Disease
• Asthma
• Ulcerative Colitis
• Hay fever
• Allergies

Asthma – Maintenance –Adult Doses

• Flex haler

Initial dose: 360 mcg via oral inhalation two times a day

Few patients: An initial dose of 180 mcg twice a day

Maximum dose: 720 mcg twice a day

• Turbuhaler

Initial dose: 400 to 2400 mcg

Maintenance dose: 200 to 400 mcg

Adult Dose for Crohn's Disease - Acute

Enteric-coated capsules

Initial dose: 9 mg orally every day in the morning for up to 8 weeks

Adult Dose for Crohn's Disease - Maintenance

Enteric-coated capsules:

6 mg orally daily morning for up to 3 months

If symptom control is maintained up to 3 months, attempt should be made to taper to complete cessation

Adult Dose - Ulcerative Colitis

Extended-release tablets:

Initial dose: 9 mg orally every day in the morning

Full Duration of therapy: Up to 8 weeks

Rectal Foam:

Active Mild to Moderate Distal Ulcerative Colitis:

1 metered dose administered rectally two times a day for 2 weeks, then 1 metered dose administered rectally once daily for 4 weeks

Pediatric Dose for Asthma - Maintenance

Inhalation Suspension to be administered via jet nebulizer:

Aged: 1 to 8 years:

Previously treatment with the bronchodilators alone: 0.5 mg via oral inhalation once a day / 0.25 mg via oral inhalation twice a day.

If previously treated with inhaled corticosteroids: 0.5 mg once daily / 0.25 mg twice a day,

Maximum daily dose: 1 mg

Previously treatment with oral corticosteroids: 1 mg once daily or 0.5 mg twice a day

Maximum daily dose: 1 mg

Flex haler Inhalation Powder (oral inhaler):

Age: 6 to 12 years:

Initial dose: 180 mcg via oral inhalation two times a day; or initial dose of 360 mcg two times a day

Maintenance dose: It is advised to increase dose after 1 to 2 weeks if there is no adequate response; once asthma stability has been achieved, doses are to be reduced to avoid the possibility of side effects

Maximum dose: 360 mcg twice a day

Turbuhaler Inhalation Powder (oral inhaler):

Aged 6 to 12 years: Initial dose: 100 to 200 mcg via oral inhalation two times a day

Maintenance dose: Lowest dose to keep patient symptom-free

Turbuhaler Inhalation Powder :

Aged over 12 years:

Initial dose: 400 to 2400 mcg via oral inhalation everyday

Maintenance dose: 200 to 400 mcg via oral inhalation twice a everyday

Once a day dosing may be considered in patients requiring 400 mcg per day in the evening

Pediatric Dose for Crohn's Disease - Acute

Aged 8 years or older; weight greater than 25 kg

Enteric-coated capsules:

9 mg orally once daily in the morning for up to 8 weeks; then 6 mg orally once daily for 2 weeks

Flex haler: 360mcg

Turbuhaler: 100 mcg, 200 mcg, 400- 2400mcg

Tablets: 6mg, 9mg

Suspension Inhaler: 0.25mg, 0.5 mg, 1 mg

Flex haler: 180mcg, 360mcg

Tablets, Suspension for nebulization, Turbuhaler, nasal spray

• Dosage Adjustments in Hepatic Impairment Patients:

No specific dose adjustment is necessary as it is not studied for Hepatic Patients. Budesonide undergoes hepatic metabolism; bioavailability increased in cirrhosis; monitor closely for signs and symptoms of hypercorticism.

• Dosage Adjustments in Pediatric Patients:

Budesonide is approved for use in the maintenance treatment of bronchospasm associated with Chronic Obstructive Pulmonary Disease. Chronic Obstructive Pulmonary Disease does not normally occur in children. The safety and effectiveness of Budesonide in pediatric patients have not been established. No Dosage Adjustments needed for Pediatric Patients

Maintaining health and smoking cessation is a must.

Avoid or restrict or limit the usage of caffeine as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Diet containing refined and high energy-dense foods, low fiber, grapes, food with a high glycemic index, saturated and trans fat food, red and processed meat, added sugar, salt, preservatives, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions should be individualized as per the patient's requirements.

Budesonide may be contraindicated during the co-administration with the following drugs:

Hypersensitivity to the ingredients of the medication

Budesonide is found to be contraindicated in the primary treatment of status asthmaticus /other acute episodes of asthma where intensive measures are required.

Steroid Independent Patients: Treatment with the recommended doses of Budesonide inhaler usually gives a therapeutic benefit within 10 days. But, certain patients might have an excessive collection of mucous secretion in the bronchioles. In such cases, a short course of oral corticosteroids about usually 1-2 weeks, should be given in addition to the aerosol administration. After the course of the oral drug administration, the inhaler alone should be sufficient for the therapy.

Steroid-Dependent Patients: Budesonide inhaler is then given in combination with the previously used oral steroid for around 10 days. Patients who require oral corticosteroids should be weaned slowly from systemic corticosteroid use after being transferred to budesonide inhaler. Prednisone reduction can be achieved by reducing the daily dose of prednisone by around 2.5 mg or equivalent dose each month to the lowest possible level during therapy alongside budesonide inhaler. Lung function i.e. mean forced expiratory volume in 1 second or morning peak expiratory flow , beta-agonist use, and asthma symptoms should be carefully monitored when oral corticosteroids are withdrawn.

Visual Disturbance:

Visual disturbance might be reported with systemic and topical corticosteroid use. If a patient is suffering from the symptoms such as blurred vision or other visual disturbances, it is advised that the patient should be referred to an ophthalmologist for evaluation of possible causes such as cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCS) which have been reported . The patient are advised to be using a short-acting inhaled bronchodilator as rescue medication to be relieved from acute asthma symptoms. As with other inhalation therapy, paradoxical bronchospasm might occur, along with an immediate increase in wheezing after dosing.

Avoid alcohol usage while on Budesonide medication as alcohol can worsen the effects of any underlying disease condition. Alcohol may worsen symptoms of Ulcerative colitis. Hence , it is recommended that one should avoid alcohol if suffering from this condition. And because budesonide is used to treat ulcerative colitis, it may be best to avoid alcohol while taking the drug.

Budesonide, like other corticosteroids, is found to be secreted in breast milk. At therapeutic doses, no effects on the baby have been anticipated. Hence, Budesonide can be used during breastfeeding. Maintenance treatment with inhaled budesonide i.e.,200 or 400 micrograms two times a day in nursing mothers with asthma, results in negligible systemic exposure to budesonide in breast-fed infants.

Pregnancy Category B.

No elevated teratogenic risk associated with the use of inhaled budesonide was found in the post-marketing studies. But In animal studies, Budesonide has been shown to induce some malformations. This might not be likely to be relevant for humans given recommended doses, but therapy with inhaled budesonide should be regularly reviewed and maintained at the lowest effective dose by the treating physician. Administration of Budesonide Inhaler during pregnancy should be used only if the benefits be weighed against the risks for the fetus.

One should avoid the regular consumption of large amounts of grapefruits and grapefruit juice while taking budesonide. This is because Grapefruit can raise the levels of budesonide in your body and lead to increased side effects.

The adverse reactions related to Budesonide can be categorized as:

Common

• Bruising easily
• Chills
• Colds
• Cough
• Diarrhea
• Fever
• General feeling of discomfort or illness
• Headache
• Hoarseness
• Joint pain
• Loss of appetite
• Muscle aches and pains
• Nausea
• Runny nose
• Shivering
• Sneezing
• Sore throat
• Sweating
• Trouble sleeping
• Unusual tiredness or weakness
• Vomiting

Less common

• Eye pain
• Irregular, pounding, or racing heartbeat or pulse
• Feeling of warmth
• Heartburn
• Increase in body movements
• Increased thirst
• Increased urge to urinate during the night
• Irregular heartbeat
• Lower back or side pain
• Mood changes
• Nervousness
• Discomfort or pain in the chest, upper stomach, or throat
• Rectal bleeding
• Seizures
• Severe constipation
• Skin rash, encrusted, scaly, and oozing
• Slow or fast heartbeat
• Stomach cramps or pain
• Sweating
• Swelling of the legs and feet
• Swelling or puffiness of the face
• Bladder pain
• Bleeding after defecation
• Bloody or cloudy urine
• Blurred vision
• Burning feeling while urinating
• Changes in vision
• Chest pain or tightness
• Cough producing mucus
• Decreased urine
• Diarrhea
• Difficult or labored breathing
• Difficult or painful urination
• Dizziness
• Dry mouth
• Trouble sleeping
• Uncomfortable swelling around the anus
• Upper abdominal or stomach pain
• Waking to urinate at night
• Weight gain or loss

Rare

• Hives, itching, or skin rash
• Bulging soft spot on the head of baby
• Change in the ability to see colors, mainly blue or yellow
• Swelling of the eyelids / around the eyes, face, lips, or tongue
• Difficulty with swallowing

The clinically relevant drug interactions of Budesonide is briefly summarized here:

In clinical studies it has been found that concurrent administration of budesonide and other drugs commonly used in the treatment of asthma did not result in an elevated frequency of adverse events. Ketoconazole which is a potent inhibitor of cytochrome P450 3A, might increase plasma levels of budesonide during concomitant administration. The clinical significance of co-administration of ketoconazole with Budesonide is not known, but caution may be warranted. Cimetidine, primarily an inhibitor of cytochrome P450, caused a slight decrease in budesonide clearance and a corresponding increase in its oral bioavailability.

The common side effects of Budesonide include the following:

• Headache
• Gas
• Vomiting
• Fatigue
• Back pain
• Muscle cramps
• Dizziness
• Runny nose, sneezing, coughing
• Nausea
• Indigestion
• Abdominal pain
• Dry, itchy skin

Pregnancy

Pregnancy Category B.

No elevated teratogenic risk associated with the use of inhaled budesonide was found in the post-marketing studies. But In animal studies, Budesonide has been shown to induce some malformations. This might not be likely to be relevant to the humans given recommended doses, but therapy with inhaled Budesonide should be regularly reviewed and maintained at the lowest effective dose by the treating physician. Administration of Budesonide Inhaler during pregnancy should be used only if the benefits be weighed against the risks for the fetus.

• Nursing Mothers

Budesonide, like other corticosteroids, is found to be secreted in breast milk. At therapeutic doses of budesonide, no side effects on the baby have been anticipated. Hence, Budesonide can be used during breastfeeding. Maintenance treatment with inhaled budesonide i.e.200 or 400 micrograms two times a day in nursing mothers with asthma, results in negligible systemic exposure to budesonide in breast-fed infants.

• Pediatric Use

Safety and efficacy of budesonide in pediatric patients aged below 6 years has not been established. Controlled clinical trial studies have shown that orally inhaled corticosteroids might lead to a reduction in growth rate in pediatric patients. This effect has found to be observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal axis suppression, which suggests that the growth velocity is a more sensitive indicator of a systemic corticosteroid exposure in pediatric patients than some commonly used tests of hypothalamic-pituitary-adrenal axis function. The long-term effects of reduction in growth velocity associated with orally inhaled corticosteroids which includes the impact on final adult height are unknown. The growth of pediatric patients who are receiving orally inhaled corticosteroids, including budesonide, should be monitored routinely via stadiometer.

• Geriatric Use

There was found to be no overall differences in safety between these older patients and younger patients. The clinical studies did not include sufficient numbers of patients of 65 years of age and over to determine differences .Thus, budesonide should be used only if the potential benefits outweighs the potential risks associated.

The physician should be vigilant about the knowledge and treatment pertaining to the identification and treatment of overdosage of Budesonide.

Acute overdose with budesonide, even in excessive doses, is not expected to be a clinical problem. When used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear.

Pharmacodynamics

Budesonide is said to be an anti-inflammatory corticosteroid which exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In a standard in vitro as well as animal models, Budesonide has approximately a 200-fold higher affinity to glucocorticoid receptor and a 1,000-fold higher topical anti-inflammatory potency than cortisol. As a measure of systemic activity, Budesonide which is found to be 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. Corticosteroids has found to have a wide range of inhibitory activities against multiple cell types and mediators which are involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids might contribute to their efficacy in asthma. Studies in asthmatic patients has shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses of Budesonide. This has been explained by a combination of a relatively high local anti-inflammatory effect, extensive first-pass hepatic degradation of orally absorbed drug of about 85–95%, and the low potency of formed metabolites. Generally, budesonide is found to have a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhalation of budesonide can occur within 24 hours of beginning treatment, although maximum benefit may not be achieved until 1 to 2 weeks, or longer.

Pharmacokinetics

• Absorption

Orally inhaled Budesonide was found to be rapidly absorbed in the lungs and peak concentration had typically reached within 20 minutes. Following oral administration of budesonide, peak plasma concentration was achieved in about 1–2 hours and the absolute systemic availability was found to be 6–13%, due to extensive first-pass metabolism. In contrast, most of the budesonide delivered to the lungs which was found to be systemically absorbed. A 34% of the metered dose was deposited in the lungs with an absolute systemic availability of 39% of the metered dose was observed in healthy patients. The peak steady-state plasma concentrations of budesonide administered by dry powder inhalation in adults suffering from asthma with an average of 0.6nmol/L and 1.6nmol/L at doses of 180 mcg and 360 mcg two times a day, respectively. In asthmatic patients, budesonide has shown a linear increase in the area under the curve and Cmax with an increasing dose, after both a single dose and repeated dosing of inhaled budesonide

• Volume of Distribution

The volume of distribution of budesonide was found to be approximately 3 L/kg. Budesonide was found to have 85–90% bound to plasma proteins. Protein binding was found to be constant over the concentration range of 1–100 nmol/L , achieved with, and exceeding, recommended inhaled doses. Budesonide has shown a little or no binding to corticosteroid-binding globulin. Budesonide is rapidly equilibrated with red blood cells in a concentration-independent manner, with a blood/plasma ratio achieved about 0.8.

• Metabolism

In vitro studies with human liver homogenates have shown that Budesonide gets rapidly and extensively metabolized into two major metabolites, formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4)-catalyzed biotransformation. It has been isolated and identified as 16alphahydroxyprednisolone and 6beta-hydroxybudesonide. The corticosteroid activity of each of the two metabolites was found to be less than 1% of that of the parent compound.

• Excretion

It has been found that the 22R form of Budesonide was cleared by the liver with systemic clearance of around 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life which is 2 to 3 hours, was found to be the same for both epimers and also independent of the dose. Budesonide was found to be excreted in urine and feces in the form of its metabolites. Approximately 60% of an intravenously radiolabeled dose was recovered in the urine while no unchanged budesonide was detected in the urine.

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