Budesonide and Formoterol Fumarate Dihydrate

Dosage Forms And Strengths

SYMBICORT is available as a metered-dose inhaler containing a combination of budesonide (80 or 160 mcg) and formoterol (4.5 mcg) as an inhalation aerosol in the following two strengths: 80/4.5 and 160/4.5. Each dosage strength contains 60 or 120 actuations per/canister. Each strength of SYMBICORT is supplied with a red plastic actuator with a gray dust cap.

Storage And Handling

SYMBICORT is available in two strengths and is supplied in the following package sizes:

Dosage Forms And Strengths

Each strength is supplied as a pressurized aluminum canister with an attached counting device, a red plastic actuator body with a white mouthpiece, and attached gray dust cap. Each 120 inhalation canister has a net fill weight of 10.2 grams and each 60 inhalation canister has a net fill weight of 6.9 grams (SYMBICORT 80/4.5) or 6 grams (SYMBICORT 160/4.5). Each canister is packaged in a foil overwrap pouch with desiccant sachet and placed into a carton. Each carton contains one canister and a Medication Guide.

The SYMBICORT canister should only be used with the SYMBICORT actuator, and the SYMBICORT actuator should not be used with any other inhalation drug product.

The correct amount of medication in each inhalation cannot be ensured after the labeled number of inhalations from the canister have been used, even though the inhaler may not feel completely empty and may continue to operate. The inhaler should be discarded when the labeled number of inhalations have been used or within 3 months after removal from the foil pouch. Never immerse the canister into water to determine the amount remaining in the canister (“float test”).

Store at controlled room temperature 20°C to 25°C (68°F to 77°F) [see USP]. Store the inhaler with the mouthpiece down.

For best results, the canister should be at room temperature before use. Shake well for 5 seconds before using.

Keep out of the reach of children. Avoid spraying in eyes.

CONTENTS UNDER PRESSURE.

Do not puncture or incinerate. Do not store near heat or open flame. Exposure to temperatures over 120°F may cause bursting. Never throw container into fire or incinerator.

Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 By: AstraZeneca Dunkerque Production, Dunkerque, France. Revised: 2017

Symbicort

SYMBICORT contains both budesonide and formoterol; therefore, the risks associated with overdosage for the individual components described below apply to SYMBICORT. In pharmacokinetic studies, single doses of 960/54 mcg (12 actuations of SYMBICORT 80/4.5) and 1280/36 mcg (8 actuations of 160/4.5), were administered to patients with COPD. A total of 1920/54 mcg (12 actuations of SYMBICORT 160/4.5) was administered as a single dose to both healthy subjects and patients with asthma. In a long-term active-controlled safety study in adolescent and adult asthma patients 12 years of age and older, SYMBICORT 160/4.5 was administered for up to 12 months at doses up to twice the highest recommended daily dose. There were no clinically significant adverse reactions observed in any of these studies.

Budesonide

The potential for acute toxic effects following overdose of budesonide is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur [see WARNINGS AND PRECAUTIONS]. Budesonide at five times the highest recommended dose (3200 mcg daily) administered to humans for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH.

Formoterol

An overdose of formoterol would likely lead to an exaggeration of effects that are typical for beta2­agonists: seizures, angina, hypertension, hypotension, tachycardia, atrial and ventricular tachyarrhythmias, nervousness, headache, tremor, palpitations, muscle cramps, nausea, dizziness, sleep disturbances, metabolic acidosis, hyperglycemia, hypokalemia. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of formoterol. No clinically significant adverse reactions were seen when formoterol was delivered to adult patients with acute bronchoconstriction at a dose of 90 mcg/day over 3 hours or to stable asthmatics 3 times a day at a total dose of 54 mcg/day for 3 days.

Treatment of formoterol overdosage consists of discontinuation of the medication together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of formoterol. Cardiac monitoring is recommended in cases of overdosage.

You should not use this medication if you are allergic to budesonide (Entocort, Pulmicort, Rhinocort) or formoterol (Foradil, Perforomist).

To make sure you can safely use budesonide and formoterol, tell your doctor if you have any of these other conditions:

• heart disease or high blood pressure;
• epilepsy or other seizure disorder;
• diabetes;
• herpes infection of the eyes;
• tuberculosis;
• any active infection;
• an electrolyte imbalance (such as low potassium levels in your blood); or
• a thyroid disorder.

FDA pregnancy category C. It is not known whether budesonide and formoterol will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Budesonide can pass into breast milk and could harm a nursing baby. Do not use budesonide and formoterol inhalation without telling your doctor if you are breast-feeding a baby.

Budesonide can affect growth in children. Talk with your doctor if you think your child is not growing at a normal rate while using this medication.

Do not give this medication to a child younger than 12 years old.

Long-term use of steroids may lead to bone loss (osteoporosis), especially if you smoke, if you do not exercise, if you do not get enough vitamin D or calcium in your diet, or if you have a family history of osteoporosis.

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Your pharmacist can provide more information about budesonide and formoterol inhalation.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in SYMBICORT, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Data from a large placebo-controlled US study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol [see WARNINGS AND PRECAUTIONS].

Systemic and inhaled corticosteroid use may result in the following:

• Candida albicans infection [see WARNINGS AND PRECAUTIONS]
• Pneumonia or lower respiratory tract infections in patients with COPD [see WARNINGS AND PRECAUTIONS]
• Immunosuppression [see WARNINGS AND PRECAUTIONS]
• Hypercorticism and adrenal suppression [see WARNINGS AND PRECAUTIONS]
• Growth effects in pediatric patients [see WARNINGS AND PRECAUTIONS]
• Glaucoma and cataracts [see WARNINGS AND PRECAUTIONS]

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

Clinical Trials Experience In Asthma

The overall safety data in adults and adolescents are based upon 10 active-and placebo-controlled clinical trials in which 3393 patients ages 12 years and older (2052 females and 1341 males) with asthma of varying severity were treated with SYMBICORT 80/4.5 or 160/4.5 taken 2 inhalations once or twice daily for 12 to 52 weeks. In these trials, the patients on SYMBICORT had a mean age of 38 years and were predominantly Caucasian (82%).

The incidence of common adverse events in Table 1 below is based upon pooled data from three 12-week, double-blind, placebo-controlled clinical studies in which 401 adult and adolescent patients (148 males and 253 females) age 12 years and older were treated with 2 inhalations of SYMBICORT 80/4.5 or SYMBICORT 160/4.5 twice daily. The SYMBICORT group was composed of mostly Caucasian (84%) patients with a mean age of 38 years, and a mean percent predicted FEV1 at baseline of 76 and 68 for the 80/4.5 mcg and 160/4.5 mcg treatment groups, respectively. Control arms for comparison included 2 inhalations of budesonide HFA metered dose inhaler (MDI) 80 or 160 mcg, formoterol dry powder inhaler (DPI) 4.5 mcg, or placebo (MDI and DPI) twice daily. Table 1 includes all adverse events that occurred at an incidence of >3% in any one SYMBICORT group and more commonly than in the placebo group with twice-daily dosing. In considering these data, the increased average duration of patient exposure for SYMBICORT patients should be taken into account, as incidences are not adjusted for an imbalance of treatment duration.

Table 1 : Adverse reactions occurring at an incidence of ≥ 3% and more commonly than placebo in the SYMBICORT groups: pooled data from three 12-week, double-blind, placebo-controlled clinical asthma trials in patients 12 years and older

Long-term safety studies in adolescent and adult patients 12 years of age and older, treated for up to 1 year at doses up to 1280/36 mcg/day (640/18 mcg twice daily), revealed neither clinically important changes in the incidence nor new types of adverse events emerging after longer periods of treatment. Similarly, no significant or unexpected patterns of abnormalities were observed for up to 1 year in safety measures including chemistry, hematology, ECG, Holter monitor, and HPA-axis assessments.

The safety data for pediatric patients aged 6 to less than 12 years is based on 1 trial of 12 weeks treatment duration. Patients (79 female and 105 male) receiving inhaled corticosteroid at trial entry were randomized to SYMBICORT 80/4.5 (n=92) or budesonide pMDI 80 mcg (n=92), 2 inhalations twice daily. The overall safety profile of these patients was similar to that observed in patients 12 years of age and older who received SYMBICORT 80/4.5 twice daily in studies of similar design. Common adverse reactions that occurred in patients treated with SYMBICORT 80/4.5 with a frequency of ≥3% and more frequently than patients treated only with budesonide pMDI 80 mcg included upper respiratory tract infection, pharyngitis, headache, and rhinitis.

Clinical Trials Experience In Chronic Obstructive Pulmonary Disease

The safety data described below reflect exposure to SYMBICORT 160/4.5 in 1783 patients. SYMBICORT 160/4.5 was studied in two placebo-controlled lung function studies (6 and 12 months in duration), and two active-controlled exacerbation studies (6 and 12 months in duration) in patients with COPD.

The incidence of common adverse events in Table 2 below is based upon pooled data from two double-blind, placebo-controlled lung function clinical studies (6 and 12 months in duration) in which 771 adult COPD patients (496 males and 275 females) 40 years of age and older were treated with SYMBICORT 160/4.5, two inhalations twice daily. Of these patients 651 were treated for 6 months and 366 were treated for 12 months. The SYMBICORT group was composed of mostly Caucasian (93%) patients with a mean age of 63 years, and a mean percent predicted FEV1 at baseline of 33%. Control arms for comparison included 2 inhalations of budesonide HFA (MDI) 160 mcg, formoterol (DPI) 4.5 mcg or placebo (MDI and DPI) twice daily. Table 2 includes all adverse events that occurred at an incidence of ≥3% in the SYMBICORT group and more commonly than in the placebo group. In considering these data, the increased average duration of patient exposure to SYMBICORT should be taken into account, as incidences are not adjusted for an imbalance of treatment duration.

Table 2 : Adverse reactions occurring at an incidence of ≥ 3% and more commonly than placebo in the SYMBICORT group: pooled data from two double-blind, placebo-controlled clinical COPD trials

Lung infections other than pneumonia (mostly bronchitis) occurred in a greater percentage of subjects treated with SYMBICORT 160/4.5 compared with placebo (7.9% vs. 5.1%, respectively). There were no clinically important or unexpected patterns of abnormalities observed for up to 1 year in chemistry, haematology, ECG, ECG (Holter) monitoring, HPA-axis, bone mineral density and ophthalmology assessments.

The safety findings from the two double-blind, active-controlled exacerbations studies (6 and 12 months in duration) in which 1012 adult COPD patients (616 males and 396 females) 40 years of age and older were treated with SYMBICORT 160/4.5, two inhalations twice daily were consistent with the lung function studies.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of SYMBICORT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some of these adverse reactions may also have been observed in clinical studies with SYMBICORT.

Cardiac disorders: angina pectoris, tachycardia, atrial and ventricular tachyarrhythmias, atrial fibrillation, extrasystoles, palpitations

Endocrine disorders: hypercorticism, growth velocity reduction in pediatric patients

Eye disorders: cataract, glaucoma, increased intraocular pressure

Gastrointestinal disorders: oropharyngeal candidiasis, nausea

Immune system disorders: immediate and delayed hypersensitivity reactions, such as anaphylactic reaction, angioedema, bronchospasm, urticaria, exanthema, dermatitis, pruritus

Metabolic and nutrition disorders: hyperglycemia, hypokalemia

Musculoskeletal, connective tissue, and bone disorders: muscle cramps

Nervous system disorders: tremor, dizziness

Psychiatric disorders: behavior disturbances, sleep disturbances, nervousness, agitation, depression, restlessness

Respiratory, thoracic, and mediastinal disorders: dysphonia, cough, throat irritation

Skin and subcutaneous tissue disorders: skin bruising

Vascular disorders: hypotension, hypertension

Read the entire FDA prescribing information for Symbicort (Budesonide and Formoterol Fumarate Dihydrate)