ipratropium bromide + salbutamol sulfateIndications Chronic obstructive pulmonary disease.

Dosage Adult: Inhalation Per inhalation contains ipratropium bromide 18 mcg and salbutamol sulfate 103 mcg: 2 inhalations 4 times/day. Max: 12 inhalations/24 hr. Per 3 mL nebulising soln contains ipratropium bromide 0.5 mg and salbutamol base 2.5 mg: Initial: 3 mL 6 hrly. Max: 3 mL 4 hrly.Click to view ipratropium bromide + salbutamol sulfate Dosage by Indications

Overdosage For action to be taken in the event of accidental overdose ... click to view ipratropium bromide + salbutamol sulfate

Contraindications

Hypersensitivity to soy lecithin or related food products e.g. peanuts.

Special Precautions

May cause paradoxical bronchospasm. Caution when used in patients who are sensitive to sympathomimetic agents. Not for treatment of acute episodes of bronchospasm. Caution when used in patients with CV disease as β-agonists may increase BP, heart rate and risk of arrhythmias. Monitor blood glucose in diabetics. Monitor serum potassium levels especially in patients who are on concurrent treatment with xanthine derivatives, steroids or diuretics. Caution when used in patients with narrow angle glaucoma, hyperthyroidism, prostatic hyperplasia, bladder neck obstruction, seizure disorders, renal or hepatic impairment. Safety and efficacy have not been established in children <12 yr. Increased risk of GI motility disturbance in patients with cystic fibrosis. Pregnancy and lactation.

Adverse Drug Reactions

Bronchitis, respiratory tract infections. Chest pain, arrhythmia, oedema, hypertension, hypokalaemia, palpitation, tachycardia. Headache, dizziness, fatigue, insomnia, tremor, nervousness. GI symptoms e.g. nausea, vomiting, diarrhoea, dyspepsia and constipation.Potentially Fatal: Anaphylactic reactions such as angioedema of tongue, lips or face and laryngospasm.

Drug Interactions May have additive anticholinergic effects when used with psychotropics; may decrease effect of propranolol. Increased CV effects (tachycardia, palpitations) when used with MAOIs, TCAs and amphetamines.

Mechanism of Action

For details of the mechanism of action, pharmacology and pharmacokinetics and toxicology ... click to view ipratropium bromide + salbutamol sulfate

MIMS Class Antiasthmatic & COPD Preparations

ATC Classification

R01AX03 - Ipratropium bromide ; Belongs to the class of other topical preparations used as nasal decongestants. R03BB01 - Ipratropium bromide ; Belongs to the class of other

inhalants used in the treatment of obstructive airway diseases, anticholinergics.

ndication & Dosage

InhalationChronic obstructive pulmonary diseaseAdult: Each inhalation contains ipratropium bromide 18 mcg and salbutamol sulfate 103 mcg: 2 inhalations 4 times daily. Max: 12 inhalations/24 hr. For nebulising solution (each 3 ml contains ipratropium bromide 0.5 mg and salbutamol base 2.5 mg): Initially, 3 ml every 6 hr. Max: 3 ml every 4 hr.

Overdosage Overdose may lead to hypokalaemia; monitor serum potassium. Other symptoms may include chest pain, hypertension and tachycardia. May treat using a cardioselective β-blocker but agent should be used with care in patients with a history of bronchospasm.

Contraindications

Hypersensitivity to soy lecithin or related food products e.g. peanuts.

Special Precautions

May cause paradoxical bronchospasm. Caution when used in patients who are sensitive to sympathomimetic agents. Not for treatment of acute episodes of bronchospasm. Caution when used in patients with CV disease as β-agonists may increase BP, heart rate and risk of arrhythmias. Monitor blood glucose in diabetics. Monitor serum potassium levels especially in patients who are on concurrent treatment with xanthine derivatives, steroids or diuretics. Caution when used in patients with narrow angle glaucoma, hyperthyroidism, prostatic hyperplasia, bladder neck obstruction, seizure disorders, renal or hepatic impairment. Safety and efficacy have not been established in children <12 yr. Increased risk of GI motility disturbance in patients with cystic fibrosis. Pregnancy and lactation.

Adverse Drug Reactions

Bronchitis, respiratory tract infections. Chest pain, arrhythmia, oedema, hypertension, hypokalaemia, palpitation, tachycardia. Headache, dizziness, fatigue, insomnia, tremor, nervousness. GI symptoms e.g. nausea, vomiting, diarrhoea, dyspepsia and constipation.Potentially Fatal: Anaphylactic reactions such as angioedema of tongue, lips or face and laryngospasm.

Drug Interactions May have additive anticholinergic effects when used with psychotropics; may decrease effect of propranolol. Increased CV effects (tachycardia, palpitations) when used with MAOIs, TCAs and amphetamines.

Storage Inhalation: Store < 25°C.

Mechanism of Action

Ipratropium bromide is an anticholinergic agent that inhibits vagally-mediated reflexes by antagonising the action of acetylcholine. It prevents the increases in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) which are brought about by

interaction of acetylcholine with the muscarinic receptors on bronchial smooth muscle. Salbutamol is a direct-acting β2-adrenergic agent. It acts on the airway smooth muscle resulting in bronchodilation.Distribution: Ipratropium: Minimally bound to plasma proteins.Excretion: Ipratropium: Elimination half-life: About 2 hr (after IV or inhalational admin). Plasma half-life of salbutamol: About 4-6 hr.

MIMS Class Antiasthmatic & COPD Preparations

ATC Classification

R01AX03 - Ipratropium bromide ; Belongs to the class of other topical preparations used as nasal decongestants. R03BB01 - Ipratropium bromide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, anticholinergics.

isosorbide mononitrate

ndication & Dosage

OralManagement of angina, Heart failureAdult: 20 mg 2-3 times daily. Dose may range from 20-120 mg daily.Elderly: Intiate at lower doses.

Administration Should be taken on an empty stomach (i.e. At least one hour before food or two hours after food).

Overdosage Symptoms: Increased intracranial pressure, with or without persistent throbbing headache, confusion and moderate fever, vertigo, palpitations, visual disturbances, nausea and vomiting.

Contraindications

Severe hypotension or anaemia, hypovolaemia, heart failure due to obstruction, or raised intracranial pressure due to head trauma or cerebral haemorrhage.

Special Precautions

Severe renal or severe hepatic impairment, hypothyroidism, malnutrition, or hypothermia. Caution in patients who are already hypotensive. May aggravate angina caused by hypertrophic cardiomyopathy. Tolerance may develop after long-term treatment. Lactation.

Adverse Drug Reactions

Hypotension, tachycardia, flushing, headache, dizziness, palpitation, syncope, confusion. Nausea, vomiting, abdominal pain. Restlessness, weakness and vertigo. Dry mouth, chest pain, back pain, oedema, fatigue, abdominal pain, constipation, diarrhoea, dyspepsia and

flatulence.Potentially Fatal: Severe hypotension and cardiac failure.

Drug Interactions Hypotensive effects may be increased when used with alcohol or vasodilators. Concurrent use with calcium channel blockers may lead to marked orthostatic hypotension.Potentially Fatal: Significant hypotension may occur when used with phosphodiesterase-5 inhibitors.Click to view more isosorbide mononitrate Drug Interactions

Lab Interference False decrease in serum cholesterol.

Pregnancy Category (US FDA) Category C: Either studies in animals have revealed adverse effects

on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Storage Oral: Store at 20-25°C.

Mechanism of Action

Isosorbide mononitrate relaxes vascular smooth muscles by stimulating cyclic-GMP. It decreases left ventricular pressure (preload) and arterial resistance (afterload).Onset: 20 min (oral as conventional tab).Duration: 8-10 hr (oral as conventional tab).Absorption: Readily absorbed from the GIT (oral); peak plasma concentrations after 1 hr.Distribution: Widely distributed: Smooth muscle cells of the blood vessels.Metabolism: Converted to inactive metabolites including isosorbide and isosorbide glucuronide.Excretion: Via urine (2% as unchanged); 4-5 hr (elimination half-life).

MIMS Class Anti-Anginal Drugs

ATC Classification

C01DA14 - Isosorbide mononitrate ; Belongs to the class of organic nitrate vasodilators. Used in the treatment of cardiac disease.

paracetamolndication & Dosage

OralMild to moderate pain and feverAdult: 0.5-1 g 4-6 hrly as necessary. Max: 4 g daily.Child: Neonate 28-32 wk post menstrual age: 20 mg/kg as a single dose then 10-15 mg/kg 8-12 hrly (max 30 mg/kg daily in divided doses); neonate >32 wk post menstrual age: 20 mg/kg as a single dose then 10-15 mg/kg 6-8 hrly (max 60 mg/kg daily in divided doses);

child 1-3 mth: 30 mg 8 hrly (max 60 mg/kg daily in divided doses); 3 mth-1 yr: 60-120 mg 4-6 hrly (max 4 doses in 24 hr); 1-5 yr: 120-250 mg 4-6 hrly (max 4 doses in 24 hr); 6-12 yr: 250-500 mg 4-6 hrly (max 4 doses in 24 hr).

CrCl (ml/min) Dosage Recommendation

10-50 6 hrly.

<10 8 hrly.

OralPost-immunisation pyrexiaChild: 2-3 mth: Initially, 60 mg repeated 4-6 hrly if necessary.

CrCl (ml/min) Dosage Recommendation

<10 8 hrly.

10-50 6 hrly.

IntravenousMild to moderate pain and feverAdult: Admin over 15 minutes. Wt >50 kg: 1 g 4-6 hrly (max 4 g daily); <50 kg: 15 mg/kg 4-6 hrly (max 60 mg/kg daily).Child: Admin over 15 min. Wt <10 kg: 7.5 mg/kg 4-6 hrly (max 30 mg/kg daily); 10-50 kg: 15 mg/kg 4-6 hrly (max 60 mg/kg daily); >50 kg: 1 g 4-6 hrly (max 4 g daily).

CrCl (ml/min) Dosage Recommendation

10-50 6 hrly.

<10 8 hrly.

RectalMild to moderate pain and feverAdult: 0.5-1 g 4-6 hrly as necessary. Max: 4 g daily.Child: Neonate 28-32 wk postmenstrual age: 20 mg/kg as a single doses then 15 mg/kg 12 hrly as necessary (max 30 mg/kg daily in divided doses); neonate >32 wk postmenstrual age: 30 mg/kg as a single dose then 20 mg/kg 8 hrly as necessary (max 60 mg/kg daily in divided doses); 1-3 mth: 30-60 mg 8 hrly (max 60 mg/kg daily in divided doses); 3-12 mth: 60-125 mg 4-6 hrly (max 4 doses in 24 hr); 1-5 yr: 125-250 mg 4-6 hrly (max 4 doses in 24 hr); 6-12 yr: 250-500 mg 4-6 hrly (max 4 doses in 24 hr; >12 yr: 500 mg 4-6 hrly (max 4g daily).

CrCl (ml/min) Dosage Recommendation

10-50 6 hrly.

<10 8 hrly.

Reconstitution: Can be diluted in 0.9% sodium chloride or 5% glucose solution up to one 1/10.Incompatibility: Do not mix with other drugs.

Administration May be taken with or without food.

Overdosage Overdosage: Consult local protocols. Early symptoms: nausea and vomiting (normally settle within 24 hr of ingestion). After 24 hr symptoms may include right subcostal pain and tenderness, usually indicates development of hepatic necrosis. Liver damage is greatest 3-4 days after ingestion and may lead to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Treatment: based on plasma concentration. Acetylcysteine protects the liver if administered within 24 hr after ingestion (most effective if given within 8 hr). Dose: 140 mg/kg orally (loading) followed by 70 mg/kg every 4 hr for 17 doses. Parenteral acetylcysteine is given to those unable to take oral dosing. Activated charcoal may be given if paracetamol is 150 mg/kg or 12 g (whichever is smaller) if it is thought that the paracetamol has been ingested within the previous hr.

Special Precautions

Renal or hepatic impairment; alcohol-dependent patients; G6PD deficiency.

Adverse Drug Reactions

Nausea, allergic reactions, skin rashes, acute renal tubular necrosis.Potentially Fatal: Very rare, blood dyscrasias (e.g. thrombocytopenia, leucopenia, neutropenia, agranulocytosis); liver damage.

Drug Interactions

Reduced absorption of cholestyramine within 1 hr of admin. Accelerated absorption with metoclopramide. Decreased effect with barbiturates, carbamazepine, hydantoins, rifampicin and sulfinpyrazone. Paracetamol may increase effect of warfarin.Potentially Fatal: Paracetamol increases the risk of liver damage in chronic alcoholics. Increased risk of toxicity with other hepatotoxic drugs or drugs which induce microsomal enzymes e.g. barbiturates, carbamazepine, hydantoins, rifampicin and sulfinpyrazone.Click to view more paracetamol Drug Interactions

Food Interaction St John's Wort may decrease effect.

Lab Interference May produce false-positive test results for 5-hydroxyindoleacetic acid.

Pregnancy Category (US FDA) Category B: Either animal-reproduction studies have not

demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an

adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

Storage Intravenous: Do not store above 30°C; do not freeze or refrigerate; if parenteral solution is diluted: use within an hr (infusion time included). Oral: Do not store above 30°C; do not freeze or refrigerate; if parenteral solution is diluted: use within an hr (infusion time included). Rectal: Do not store above 30°C; do not freeze or refrigerate; if parenteral solution is diluted: use within an hr (infusion time included).

Mechanism of Action

Paracetamol exhibits analgesic action by peripheral blockage of pain impulse generation. It produces antipyresis by inhibiting the hypothalamic heat-regulating centre. Its weak anti-inflammatory activity is related to inhibition of prostaglandin synthesis in the CNS.Onset: <1 hr.Duration: 4-6 hr.Absorption: Incomplete; depends upon dosage form. Time to peak, serum: oral: 10-60 min; may be delayed in acute overdoses. Decreased rate of absorption with food.Distribution: Present in most body tissues; crosses the placenta and enters the breast milk. Protein binding: 8-43% (at toxic doses).Metabolism: Hepatic via glucuronic and sulphuric acid conjugation. At normal therapeutic levels, glucuronide metabolites are metabolised to reactive intermediate (acetylimidoquinone) which is conjugated with glutathione and inactivated; at toxic doses, glutathione conjugation is insufficient leading to increased acetylimidoquinone which may cause hepatic cell necrosis.Excretion: Plasma half-life: 2.7 hr (adults); 1.5-2 hr (infants and children); 3.5 hr (neonates). Neonates, infants and children up ≤10 yr excrete less glucuronide than adults. Half-life may be longer after toxic doses. Excreted mainly via urine (2- 5% unchanged; 55% as glucuronide metabolites). Total body clearance: 18 L/hr.

MIMS Class Analgesics (Non-Opioid) & Antipyretics

ATC Classification

N02BE01 - Paracetamol ; Belongs to the class of anilide preparations. Used to relieve pain and fever.

Symbicort

ManufacturerAstraZeneca

Distributor Zuellig

Contents Budesonide, formoterol fumarate

Indications Asthma: Treatment of asthma where use of a combination (inhaled corticosteroid and long-acting β2-agonist) is appropriate.

COPD: Regular treatment of patients with moderate to severe chronic obstructive pulmonary disese (COPD), with frequent symptoms and history of exacerbations.

Dosage The dosage of Symbicort should be individualized according to disease severity.

When control has been achieved, the dose should be titrated to the lowest dose at which effective control of symptoms is maintained.

Symbicort Maintenance and Reliever Therapy (SMART): Symbicort is taken as both regular maintenance treatment and also as needed in response to symptoms. The needed inhalations provide both rapid relief and improved asthma control. Patients should be advised to have Symbicort available for rescue use at all times. A separate inhaler for rescue use is not necessary.

Clinical studies have demonstrated that Symbicort maintenance and reliever therapy provides clinically meaningful reductions in severe exacerbations while maintaining symptom control, compared to Symbicort maintenance therapy with a separate rapid-acting bronchodilator (see Pharmacology under Actions).

Asthma: 80/4.5 mcg/dose and 160/4.5 mcg/dose: Adults and Adolescents (≥12 years): The recommended maintenance dose is 2 inhalations/day, given either as 1 inhalation in the morning and evening or as 2 inhalations in either the morning or evening. For some patients, a maintenance dose of 2 inhalations (160/4.5 mcg/dose) twice daily may be appropriate. Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Not more than 6 inhalations should be taken on any single occasion.

Children (≥4 years): The usual maintenance dose is 1 inhalation once daily. Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Not more than 4 inhalations should be taken on any single occasion.

A total daily dose of >8 inhalations for adults and adolescents and 4 inhalations for children is normally not needed, however a total daily dose of up to 12 inhalations for adults and adolescents and 8 inhalation for children can be used temporarily. If the patient experiences deteriorating symptoms after taking the appropriate maintenance therapy and additional as needed inhalations, the

patient should be reassessed for alternative explanations of persisting symptoms.

Maintenance Therapy: Symbicort taken as regular maintenance treatment, with a separate rapid-acting bronchodilator as rescue. Patients should be advised to have their separate rapid-acting bronchodilator available for rescue used at all times.

Adults (≥18 years): 1-2 inhalations once or twice daily. In some cases, up to a maximum of 4 inhalations twice daily may be required as maintenance dose or temporarily during worsening of asthma.

Adolescents (12-17 years): 1-2 inhalations once or twice daily. During worsening of asthma, the dose may temporarily be increased to a maximum of 4 inhalations twice daily.

Children (≥4 years): 1-2 inhalations twice daily of 80/4.5 mcg/dose or 1 inhalation twice daily of 160/4.5 mcg/dose. Maximum Daily Dose: 4 inhalations of 80/4.5 mcg/dose or 2 inhalations of 160/4.5 mcg/dose.

Increasing use of a separate rapid-acting bronchodilator indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy.

320 mcg/9 mcg/dose: Recommended Dose: Adults (≥18 years): 1 inhalation once or twice daily. In some cases, up to a maximum of 2 inhalations twice daily may be required as maintenance dose or temporarily during worsening of asthma.

Adolescents (12-17 years): 1 inhalation once or twice daily. During worsening of asthma, the dose may temporarily be increased to a maximum of 2 inhalations twice daily.

Children: Efficacy and safety have not been studied in children for Symbicort 320/9 mcg/inhalation.

Symbicort 320/9 mcg/inhalation should be used as maintenance therapy only. Lower strengths are available for the maintenance and reliever therapy regimen.

COPD: 160/4.5 mcg/dose: Adults (≥18 years): 2 inhalations twice daily. Maximum Daily Dose: 4 inhalations.

320/9 mcg/dose: Adults (≥18 years): 1 inhalation twice daily. Maximum Daily Dose: 2 inhalations.

General Information: The patient should be instructed to take the maintenance dose of Symbicort even when asymptomatic for optimal benefit.

There are no special dosing requirements for elderly patients.

There are no data available for use of Symbicort in patients with hepatic or renal impairment. As budesonide and formoterol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver diseases.

Overdosage An overdose of formoterol would likely lead to effects that are typical for β2-adrenergic agonists: Tremor, headache, palpitations and tachycardia. Hypotension, metabolic acidosis, hypokalemia and hyperglycemia may also occur. Supportive and symptomatic treatment may be indicated. A dose of 90 mcg administered during 3 hrs in patients with acute bronchial obstruction raised no safety concerns.

Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. When used chronically in excessive doses, systemic glucocorticosteroid effects may appear.

Contraindications Hypersensitivity to budesonide, formoterol or inhaled lactose.

Special Precautions It is recommended that the dose is tapered when long-term treatment is discontinued and should not be stopped abruptly.

If patients find the treatment ineffective or exceed the highest recommended dose of Symbicort, medical attention must be sought.

Sudden and progressive deterioration in control of asthma or COPD is potentially life-threatening and the patient should undergo urgent medical assessment. In this situation, consideration should be given to the need for increased therapy with corticosteroids eg, a course of oral corticosteroids or antibiotic treatment if an infection is present.

Treatment with Symbicort should not be initiated to treat a severe exacerbation.

Physicians should closely follow the growth of children and adolescents taking long-term corticosteroids by any route and

weigh the benefits of the corticosteroid therapy against the possible risk of growth suppression (see Pharmacology under Actions).

Particular care is needed in patients transferring from oral steroids, since they may remain at risk of impaired adrenal function for a considerable time. Patients who have required high dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Symbicort should be administered with caution in patients with severe cardiovascular disorders (including heart rhythm abnormalities), diabetes mellitus, untreated hypokalemia or thyrotoxicosis.

High doses of β2-agonists can lower s-potassium by inducing a redistribution of potassium from the extracellular to the intracellular compartment, via stimulation of Na+/K+-ATPase in muscle cells. The clinical importance of this effect is uncertain.

Symbicort turbuhaler contains lactose (<1 mg/inhalation). This amount does not normally cause problems in lactose-intolerant people.

Effects on the Ability to Drive or Operate Machinery: Symbicort is not expected to adversely affect the ability to drive or use machines.

Use in pregnancy & lactation: For Symbicort or the concomitant treatment with budesonide and formoterol, no clinical data on exposed pregnancies are available. Data from an embryo-fetal development study in rat, using the budesonide/formoterol pMDI formulation, showed no evidence of any additional effect from the combination or evidence of any additional effects from the combination or evidence of any effect attributable to the excipients on the rodent.

There are no adequate data from use of formoterol in pregnant women. In animal studies, formoterol has caused adverse effects in reproduction studies at very high systemic exposure levels (see

Toxicology: Preclinical Safety Data under Actions).

Data on approximately 2500 exposed pregnancies indicate no increased teratogenic risk associated with the use of inhaled budesonide.

During pregnancy, Symbicort turbuhaler should only be used after special consideration especially during the first 3 months and shortly before delivery. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used.

A Clinical Pharmacology study has shown that inhaled budesonide is excreted in breast milk. However, budesonide was not detected in nursing infant blood samples. Based on pharmacokinetic parameters, the plasma concentration in the child is estimated be <0.17% of the mother's plasma concentration. Consequently, no effects due to budesonide are anticipated in breastfed children whose mothers are receiving therapeutic doses of Symbicort. It is not known whether formoterol passes into human breast milk. In rats, small amounts of formoterol have been detected in maternal milk. Administration of Symbicort to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

Adverse Drug Reactions

Since Symbicort contains both budesonide and formoterol, the same type and intensity undesirable effects as reported for these substances may occur. No increased incidence of adverse reactions has been seen following concurrent administration of the 2 compounds. The most common drug-related adverse reactions are pharmacologically predictable side effects of β2-agonist therapy eg, tremor and palpitations. These tend to be mild and disappear within a few days of treatment.

Adverse reactions, which have been associated with Symbicort are given as follows. These are classified by frequency and system organ class (SOC) as: Common (1-10%); uncommon (0.1-1%); rare (0.01-0.1%); very rare (<0.01%):

Common (1-10%): Cardiac Disorder: Palpitations.

Infections and Infestations: Candida infections in oropharynx.

Nervous System Disorders: Headache, tremor.

Respiratory, Thoracic and Mediastinal Disorders: Mild irritation

in the throat, coughing, hoarseness.

Uncommon (0.1-1%): Cardiac Disorders: Tachycardia.

Gastrointestinal Disorders: Nausea.

Musculoskeletal and Connective Tissue Disorders: Muscle cramps.

Nervous System Disorders: Dizziness.

Psychiatric Disorders: Agitation, restlessness, nervousness, sleep disturbances.

Rare (0.01-0.1%): Cardiac Disorders: Cardiac arrhythmias eg, atrial fibrillation, supraventricular tachycardia, extrasystoles.

Immune System Disorders: Immediate and delayed hypersensitivity reactions eg, dermatitis, exanthema, urticaria, pruritus, angioedema and anaphylactic reaction.

Respiratory, Thoracic and Mediastinal Disorder: Bronchospasm.

Skin and Subcutaneous Tissue Disorder: Skin bruising.

Very rare (<0.01%): Cardiac Disorders: Angina pectoris.

Endocrine Disorders: Signs or symptoms of systemic glucocorticosteroid effects eg, hypofunction of the adrenal gland.

Metabolism and Nutrition Disorder: Hyperglycemia.

Psychiatric Disorders: Depression, behavioral disturbances.Click to view ADR Monitoring Website

Drug Interactions Pharmacokinetic Interactions: The metabolism of budesonide is primarily mediated by the enzyme CYP3A4. Inhibitors of this enzyme eg, ketoconazole, may therefore increase systemic exposure to budesonide. This is of limited clinical importance for short-term (1-2 weeks) treatment with ketoconazole, but should be taken into consideration during long-term treatment with ketoconazole.

Pharmacodynamic Interactions: Beta-adrenergic blockers (including eye drops) can weaken or inhibit the effect of

formoterol.

Budesonide and formoterol have not been observed to interact with any other drugs used in the treatment of asthma.View more drug interactions with Symbicort

Pregnancy Category (US FDA)

Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Caution For Usage Instruction for Correct Use of Turbuhaler: Turbuhaler is inspiratory flow-driven, which means that when the patient inhales through the mouthpiece, the substance will follow the inspired air into airways.

Note: It is important to instruct the patient to carefully read the instruction for use in the patient information leaflet which is packed together with each inhaler; to breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs; never to breathe out through the mouthpiece; to replace cover of Symbicort after use; to rinse the mouth out with water after inhaling the maintenance dose to minimize the risk of oropharyngeal thrush.

The patient may not taste or feel any medication when using turbuhaler due to small amount of drug dispensed.

Turbuhaler is a multidose inhaler from which very small amounts of powder are administered. When breathing in a turbuhaler, the powder is delivered to the lungs. It is therefore important to inhale forcefully and deeply through the mouthpiece.

How to Prepare a New Inhaler for Use: Before using turbuhaler, prepare the inhaler for use.

1. Unscrew and lift off the cover. A rattling sound is heard when the patient unscrew the cover.

2. Hold the inhaler upright with the red grip downwards. Do not hold the mouthpiece when turning the grip. Turn the grip as far as it will go in one direction and then back again as far as it will go. It does not matter which way to turn first. During this procedure,

patient will hear a click. Perform the procedure twice.

The inhaler is ready for use and the patient should not repeat the procedure again. To take a dose, continue according to the instructions as follows.

How to Use Symbicort Turbuhaler: To administer 1 dose simply follow the following instructions:

1. Unscrew and lift off the cover. A rattling sound is heard when the patient unscrew the cover.

2. Hold the inhaler upright with the red grip downwards. Do not hold the mouthpiece when the patient turn the grip. To load the inhaler with a dose turn the grip as far as it will go in one direction and then back again as far as it will go. It does not matter which way the patient turn first. During this procedure the patient will hear a click.

3. The patient should breathe out. Do not breathe out through the mouthpiece.

4. Place the mouthpiece gently between the teeth, close the patients' lips and inhale forcefully and deeply through the mouth. Do not chew or bite on the mouthpiece.

5. Remove inhaler from the mouth, before breathing.

6. If >1 dose has been prescribed, repeat steps 2-5.

7. Replace the cover by screwing it back on tightly.

8. Rinse the patient's mouth with water. Do not swallow.

Note: The patient should not try to remove the mouthpiece since it is fixed to the inhaler. The mouthpiece can be rotated, but do not twist it unnecessarily.

As the amount of powder dispensed is very small, the patient may not be able to taste it after inhalation.

However, the patient can still inhale the dose if the patient have followed the instructions.

If the patient by mistake perform the loading procedure more than

once before taking the dose, the patient will still receive only 1 dose. The dose indicator will, however, register all the loaded doses.

The sound heard if the patient shake the inhaler is not produced by the medication but by a drying agent.

When to Replace the Inhaler: The dose indicator tells the patient approximately how many doses are left in the inhaler, starting with 60 when full.

The indicator is marked in intervals of 10 doses. Therefore it does not show the loading of each individual dose.

The patient should be reassured that turbuhaler delivers the dose even if they may not notice a movement in the dose indicator.

For the last 10 doses, the background of the indicator is red. When the zero reaches the middle of the window, it is time for the patient to discard the inhaler.

Note that even when the dose indicator registers zero, it is still possible to turn the grip. However, the indicator stops moving and the zero remains in the window.

Cleaning: Wipe the outside of the mouthpiece regularly (once a week) with a dry tissue. Do not use water or other liquids when cleaning the mouthpiece.

Disposal: Always be sure to dispose of the used Turbuhaler responsibly, since some of the medicine will remain inside it.

Storage Store at a temperature not exceeding 25°C (80 and 160/4.5 mcg/dose) or 30°C (320/9 mcg/dose). Store with cover tightened.

Description Each delivered dose of Symbicort contains budesonide 80, 160 or 320 mcg/inhalation and formoterol fumarate dihydrate 4.5 or 9 mcg/inhalation. It also contains lactose monohydrate (which may contain milk protein residue) as excipient.

Symbicort Turbuhaler is a multidose inspiratory flow driven, dry powder inhaler containing white powder.

For mono products, the corresponding metered doses are 100 mcg/inhalation for Budecort Turbuhaler (budesonide) with 6 or 12 mcg/inhalation for Oxis Turbuhaler (formoterol fumarate

dihydrate).

Mechanism of Action

Pharmacotherapeutic Group: Adrenergics and other drugs for obstructive airway diseases. ATC Code: R03AK07.Pharmacology: Mechanism of Action: Symbicort contains formoterol and budesonide, which have different modes of action and show additive effects in terms of reduction of asthma and chronic obstructive pulmonary disease (COPD) exacerbations. The respective mechanisms of action of both drugs are discussed as follows. The specific properties of budesonide and formoterol allow the combination to be used both as maintenance and reliever therapy, and as maintenance treatment of asthma.Budesonide: A glucocorticosteroid which when inhaled has a rapid (within hrs) and dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer asthma exacerbations. Inhaled budesonide has less severe adverse effects than systemic corticosteroids. The exact mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown.Formoterol: A selective β2-adrenergic agonist that when inhaled results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect is dose dependent, with an onset of effect within 1-3 min. The duration of effect is at least 12 hrs after a single dose.Clinical Efficacy for Symbicort Maintenance and Reliever Therapy in Asthma: A total of 12,076 asthma patients were included in 5 double-blind clinical studies (4447 were randomized to Symbicort maintenance and reliever therapy) for 6 or 12 months. Patients were required to be symptomatic despite daily use of inhaled glucocorticosteroids. Symbicort maintenance and reliever therapy provided statistically significant and clinically meaningful reductions in severe exacerbations by prolonging time to first event and reducing the event rate (see table), as compared with all comparator treatments, including Symbicort at a higher maintenance dose (in Study 735). Symptom control, lung function and reliever use were similar compared with a higher maintenance dose of Symbicort, and all 3 parameters were improved compared with Symbicort at the same maintenance dose or budesonide at a 2-4 times higher maintenance dose.

Click on icon to see table/diagramIn Study 735, Symbicort maintenance and reliever therapy significantly prolonged the time to the first exacerbation (see Figure 1) compared to the other treatment groups. The rate of

exacerbations was reduced by 28% compared to twice the maintenance dose of Symbicort with terbutaline as reliever. Lung function, symptom control and reliever use were similar in all treatment groups.

Click on icon to see table/diagramIn Study 734, Symbicort maintenance and reliever therapy prolonged the time to the first exacerbation compared to Symbicort at the same maintenance dose with either formoterol or terbutaline as reliever (see Figure 2). The rate of exacerbations was reduced by 33% and 48%, respectively. Symptoms and reliever use were reduced and lung function improved, compared with both comparator treatments.

Click on icon to see table/diagramIn studies 673, 668 and 667, Symbicort maintenance and reliever therapy prolonged the time to the first exacerbation compared to Symbicort at the same maintenance dose with terbutaline as reliever and compared to a 2- to 4-fold higher maintenance dose of budesonide with terbutaline as reliever. Across the 3 studies, the rate of exacerbations was reduced by 45-76%. Symptoms and reliever use were reduced and lung function improved compared with all other treatments. For children (118 randomized to Symbicort maintenance and reliever therapy in Study 673), the exacerbation rate was reduced by 70-79%.In the 5 long-term studies, patients (adults and adolescents) receiving Symbicort maintenance and reliever therapy was allowed 12 inhalations/day (maintenance and as needed) without being reassessed. On average, no reliever inhalation was used on 57% of treatment days and 0-2 reliever inhalations on 87% of treatment days. There was no sign of development of tolerance over time.In 2 studies with patients seeking medical attention due to acute asthma symptoms, Symbicort provided rapid and effective relief of bronchoconstriction similar to salbutamol and formoterol.Clinical Efficacy in Asthma for Symbicort Maintenance Therapy: Clinical studies have shown that the addition of formoterol to budesonide improved asthma symptoms and lung function and reduced exacerbations. The effect on lung function of Symbicort, given as a maintenance dose only, was equal to that of budesonide and formoterol in separate inhalers in adults and exceeded that of budesonide alone in adults and children. All treatment arms used a short-acting β2-agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.

Clinical Efficacy in COPD: In two 12-month studies in patients with COPD, Symbicort was superior to placebo, formoterol and budesonide regarding lung function and showed a significant reduction in the exacerbation rate compared with placebo and formoterol. Thus, the contribution of both budesonide and formoterol to the effect of Symbicort was demonstrated. Symbicort was also superior to placebo regarding symptoms and quality of life. The treatment was well tolerated.Pharmacokinetics: Absorption: Symbicort and the corresponding monoproducts (Budecort Turbuhaler and Oxis Turbuhaler, respectively) have been shown to be bioequivalent with regard to systemic exposure of budesonide and formoterol, respectively.There was no evidence of pharmacokinetic interactions between budesonide and formoterol.Pharmacokinetic parameters for the respective substances were comparable after the administration of budesonide and formoterol as monoproducts or as budesonide/formoterol.Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached within 30 min after inhalation.In studies, mean lung deposition of budesonide after inhalation via Budecort or Pulmicort Turbuhaler ranged from 32-44% of the delivered dose. The systemic bioavailability is approximately 49% of the delivered dose. In children the plasma concentrations and lung deposition fall in the same range as in adults.Inhaled formoterol is rapidly absorbed and the maximum plasma concentration is reached within 10 min after inhalation. In studies, the mean lung deposition of formoterol after inhalation via Oxis Turbuhaler ranged from 28-49% of the delivered dose. The systemic availability is about 61% of the delivered dose.Distribution and Metabolism: Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. Volume of distribution is about 4 L/kg for formoterol and 3 L/kg for budesonide. Formoterol is inactivated via conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates). Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone is <1% of that of budesonide. There are no indications of any metabolic interactions or any displacement reactions between formoterol and budesonide.Elimination: The major part of a dose of formoterol is eliminated by metabolism in the liver followed by renal excretion. After inhalation, 8-13% of the delivered dose of formoterol is excreted

unmetabolized in the urine. Formoterol has a high systemic clearance (approximately 1.4 L/min) and the terminal elimination t½ averages 17 hrs.Budesonide is eliminated via metabolism mainly catalyzed by the enzyme CYP3A4. The metabolites of budesonide are excreted in urine as such or in conjugated form. Only negligible amounts of unchanged budesonide have been detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min) and the plasma elimination t½ after IV dosing averages 4 hrs.Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal t½ of budesonide after inhalation is approximately 2.3 hrs in asthmatic children. The pharmacokinetics of formoterol in children has not been studied.The pharmacokinetics of budesonide or formoterol in elderly and patients with renal failure is unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.Toxicology: Preclinical Safety Data: The toxicity observed in animal studies with budesonide and formoterol was similar whether budesonide or formoterol were given in combination or separately. The effects were associated with pharmacological actions and dose dependent.In animal reproduction studies, corticosteroids eg, budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant in humans at the recommended doses (see Use in pregnancy & lactation under Precautions). Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure and implantation losses as well as decreased early postnatal survival and birth weight at considerably higher systemic exposures than those reached during clinical use. However, these animal experimental results do not seem to be relevant to man.

MIMS Class Antiasthmatic & COPD Preparations

ATC Classification R03AK07 - Formoterol and other drugs for obstructive airway diseases ; Belongs to the class of adrenergics and other inhalants used in the treatment of obstructive airway diseases.

Poison Schedule [?] Rx

Presentation/Packing

Turbuhaler 80/4.5 mcg x 60 doses. 160/4.5 mcg x 60 doses. 320/9 mccg x 60 doses.