Advil Cold and Sinus Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................. 2

Table of Contents ................................................................................................................. 2

Part 1: Healthcare Professional Information.......................................................................... 6

1. 1.

   Indications ................................................................................................................ 6

   1.1 Pediatrics ...................................................................................................................... 6

   1.2 Geriatrics ...................................................................................................................... 6

2. 2. Contraindications ...................................................................................................... 6
3. 3. Serious Warnings and Precautions Box ...................................................................... 8
4. 4.

   Dosage and Administration ....................................................................................... 8

   4.1 Dosing Considerations ................................................................................................. 8

   4.2 Recommended Dose and Dosage Adjustment ............................................................ 8

   4.4 Administration ............................................................................................................. 9

   4.5 Missed Dose ................................................................................................................. 9

5. 5. Overdose .................................................................................................................. 9

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

1. 6. Dosage Forms, Strengths, Composition and Packaging ............................................. 12
2. 7.

   Warnings and Precautions ....................................................................................... 14

   General ............................................................................................................................. 14

   Carcinogenesis and Mutagenesis..................................................................................... 14

   Cardiovascular .................................................................................................................. 14

   Dependence, Tolerance and/or Abuse Liability ............................................................... 15

   Ear/Nose/Throat .............................................................................................................. 16

   Endocrine and Metabolism .............................................................................................. 16

   Fluid and Electrolyte Balance ........................................................................................... 16

   Gastrointestinal ................................................................................................................ 16

   Genitourinary ................................................................................................................... 17

   Hematologic ..................................................................................................................... 17

   Hepatic/Biliary/Pancreatic ............................................................................................... 18

   Immune ............................................................................................................................ 18

   Monitoring and Laboratory Tests - Pregnancy ................................................................ 19

   Neurologic ........................................................................................................................ 19

   Ophthalmologic ................................................................................................................ 19

   Peri-Operative Considerations ......................................................................................... 19

   Psychiatric ........................................................................................................................ 19

   Renal ................................................................................................................................ 19

   Respiratory ....................................................................................................................... 20

   Sensitivity/Resistance ...................................................................................................... 20

   Skin ................................................................................................................................... 20

   7.1 Special Populations .................................................................................................... 21

   7.1.1 Pregnancy ......................................................................................................... 21

   7.1.2 Breastfeeding ................................................................................................... 22

   7.1.3 Pediatrics .......................................................................................................... 22

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

7.1.4 Geriatrics ......................................................................................................... 22

1. 8.

   Adverse Reactions ................................................................................................... 23

   8.1 Adverse Reaction Overview ....................................................................................... 23

   8.2 Clinical Trial Adverse Reactions ................................................................................. 23

   8.2.1 Clinical Trial Adverse Reactions – Pediatrics........................................................... 23

   8.5 Post-Market Adverse Reactions ................................................................................. 24

2. 9.

   Drug Interactions .................................................................................................... 32

   9.1 Serious Drug Interactions........................................................................................... 32

   9.2 Drug Interactions Overview ....................................................................................... 33

   9.3 Drug-Behaviour Interactions ...................................................................................... 33

   9.4 Drug-Drug Interactions .............................................................................................. 33

   9.5 Drug-Food Interactions .............................................................................................. 37

   9.6 Drug-Herb Interactions .............................................................................................. 37

   9.7 Drug-Laboratory Test Interactions ............................................................................. 37

3. 10.

   Clinical Pharmacology ............................................................................................. 38

   10.1 Mechanism of Action ............................................................................................... 38

   10.2 Pharmacodynamics .................................................................................................. 38

   10.3 Pharmacokinetics ..................................................................................................... 40

4. 11. Storage, Stability and Disposal ................................................................................. 44

Part 2: Scientific Information .............................................................................................. 45

1. 13. Pharmaceutical Information .................................................................................... 45
2. 14.

   Clinical Trials ........................................................................................................... 46

   14.1 Clinical Trials by Indication....................................................................................... 46

   14.2 Comparative Bioavailability Studies ........................................................................ 48

3. 15. Microbiology ........................................................................................................... 50
4. 16. Non-Clinical Toxicology ........................................................................................... 50

Patient Medication Information ......................................................................................... 53

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Patient Medication Information ......................................................................................... 60

Patient Medication Information ......................................................................................... 67

Patient Medication Information ......................................................................................... 74

Patient Medication Information ......................................................................................... 81

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Part 1: Healthcare Professional Information

1. Indications

Advil Cold And Sinus, Advil Cold And Sinus Daytime (Ibuprofen and Pseudoephedrine Hydrochloride Tablets), Advil Cold & Sinus Liqui-Gels and Advil Cold & Sinus Extra Strength Liqui-Gels (Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules) are indicated for:

• the temporary relief of symptoms associated with the common cold, including nasal congestion, sore throat pain, headache, fever, and minor body aches and pains.

Children’s Advil Cold (Ibuprofen and Pseudoephedrine Hydrochloride Suspension) is indicated for:

• the temporary relief of cold symptoms, including nasal and sinus congestion, fever, stuffy nose, headache, sore throat pain, and minor aches and pains.

1.1 Pediatrics

Pediatrics (<12 years of age): No data for Advil Cold And Sinus, Advil Cold And Sinus Daytime, Advil Cold & Sinus Liqui-Gels and Advil Cold & Sinus Extra Strength Liqui-Gels are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

Pediatrics (6 – 12 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Children’s Advil Cold in pediatric patients has been established. Therefore, Health Canada has authorized an indication for pediatric use.

Pediatrics (<6 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for Children’s Advil Cold for children under 6 years of age.

1.2 Geriatrics

Geriatrics (>65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. Therefore, the use of Advil Cold And Sinus, Advil Cold And Sinus Daytime, Advil Cold & Sinus Liqui-Gels and Advil Cold & Sinus Extra Strength Liqui-Gels in this population is not recommended. (See 7 Warnings and Precautions – 7.1.4 Geriatrics and 4 Dosage and Administration).

2. Contraindications

• Active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system, such as ulcerative colitis and Crohn’s disease.
• Known or suspected hypersensitivity to ibuprofen or other non-steroidal anti-inflammatory (NSAID) drugs. Patients who are hypersensitive to this drug or any ingredient in the formulation or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

• and Packaging. The potential for cross-reactivity between different NSAIDs must be kept in mind.
• Advil Cold And Sinus, Advil Cold And Sinus Daytime, Advil Cold & Sinus Liqui-Gels, Advil Cold & Sinus Extra Strength Liqui-Gels or Children’s Advil Cold should not be used in patients with the complete or partial syndrome of nasal polyps, or in whom angioedema syndrome, asthma, anaphylaxis, bronchospastic reaction, urticaria, rhinitis or other allergic manifestations are precipitated by acetylsalicylic acid (ASA) or other nonsteroidal anti-inflammatory agents. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse effects.
• Significant hepatic impairment or active liver disease.
• Severely impaired or deteriorating renal function (creatinine clearance <30 mL/min). Individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored.
• Ibuprofen is not recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects (See 9.4 Drug-Drug Interactions – ASA and Other NSAID’s).
• Children (i.e. 18 years of age and younger) with kidney disease and children who have suffered significant fluid loss due to vomiting, diarrhea or lack of fluid intake, should not be given ibuprofen.
• Advil Cold And Sinus, Advil Cold And Sinus Daytime, Advil Cold & Sinus Liqui-Gels, Advil Cold & Sinus Extra Strength Liqui-Gels and Children’s Advil Cold should not be used by patients who have known or suspected hypersensitivity to pseudoephedrine or other sympathomimetic amines, are taking or have taken monoamine oxidase inhibitor (MAOI) drugs within the last 14 days, have been diagnosed with severe hypertension, or have severe coronary artery disease (See 9 Drug Interactions).
• Ibuprofen should not be used during the third trimester of pregnancy because of risk of premature closure of the ductus arteriosus, and prolonged parturition.
• Ibuprofen is contraindicated in patients with systemic lupus erythematosus, as an anaphylaxis-like reaction with fever may occur, particularly when ibuprofen has been administered previously.
• Known hyperkalemia (see 7 Warnings and Precautions - Fluid and Electrolyte Balance)
• Immediately before or following heart surgery.
• In patients with thyroid disease.
• In patients with Raynaud’s Syndrome.
• In patients who are taking oxazolidinone class of antibiotics including linezolid.

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

3. Serious Warnings and Precautions Box

4. Dosage and Administration

4.1 Dosing Considerations

• Do not take for fever for more than 3 days or for more than 5 days for cold symptoms/pain.
• Do not take for sore throat pain for more than 2 days.
• Patients older than 65 years should not use Advil Cold & Sinus products.
• The lowest effective dose should be used for the shortest possible duration.

4.2 Recommended Dose and Dosage Adjustment

Advil Cold And Sinus and Advil Cold And Sinus Daytime

• Adults under 65 years of age and children over 12 years of age: Take 1 or 2 caplets every 4 to 6 hours as needed. No more than 6 caplets are to be taken in 24 hours, unless directed by a physician.

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Advil Cold & Sinus Liqui-Gels

• Adults under 65 years of age and children over 12 years of age: Take 1 or 2 Liqui-gels every 4 to 6 hours as needed. Maximum 6 Liqui-gels in 24 hours, unless directed by a physician.

Advil Cold & Sinus Extra Strength Liqui-Gels

• Adults under 65 years of age and children over 12 years of age: Take 1 Liqui-gel every 4 to 6 hours as needed. Maximum 3 Liqui-gels in 24 hours, unless directed by a physician.

Children’s Advil Cold

• The appropriate dose can be determined by using either the child’s age or weight. If possible, use weight to dose, otherwise use age. Use only the measuring device provided.
• The dosages are as follows:

• The suspension should be shaken well before pouring the dose. The adult who administers treatment should ensure that the child takes the entire contents of the dosage cup.
• Doses may be repeated every 6 hours while symptoms persist, up to 4 doses a day, or as directed by a physician.

4.4 Administration

See 4.2 Recommended Dose and Dosage Adjustment.

4.5 Missed Dose

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take your medicine and skip the missed dose. Do not take two doses at the same time.

5. Overdose

Symptoms of Overdosage

Advil Cold And Sinus, Advil Cold And Sinus Daytime, Advil Cold & Sinus Liqui-Gels, Advil Cold & Sinus Extra Strength Liqui-Gels and Children’s Advil Cold contain ibuprofen and pseudoephedrine

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

hydrochloride. The toxicity of overdose is dependent upon the amount of the product ingested, and the time elapsed since ingestion; individual responses may vary, thus making it necessary to evaluate each case separately. The most frequently reported symptoms of the two combination drugs in situations of overdose include abdominal pain, nausea, vomiting, lethargy and drowsiness, headache, tinnitus, CNS depression, seizures, anxiety, hyper-excitability, irritability, restlessness, psychosis, delirium, convulsions, dilated pupils, tachycardia, bradychardia, hypertension or hypotension, atrial fibrilation, abnormal speech, visual and tactile hallucinations, ataxia, and hyper-reflexia. Metabolic acidosis, electrolyte disturbances, coma, acute renal failure, and apnoea (primarily in very young children), hyperkalemia and respiratory depression may rarely occur.

Treatment of Overdose

In cases of acute overdose, the stomach should be emptied through induction of emesis (in alert patients only) or gastric lavage. Due to the rapid absorption of pseudoephedrine and ibuprofen from the gut, emesis is most effective if initiated within 30 minutes of ingestion. Orally administered activated charcoal may help in reducing the absorption of drugs when given less than 2 hours following ingestion. There is some evidence that repeated administration of activated charcoal may bind the medication that has diffused from the circulation. Inducing diuresis may be helpful. The treatment of acute overdose is primarily supportive. Cardiac status should be monitored, and the serum electrolytes measured. If there are signs of cardiac toxicity, propranolol may be administered intravenously. A slow infusion of a dilute solution of potassium chloride should be initiated in the event of a drop in the serum potassium level. Despite hypokalemia, the patient is unlikely to be potassium depleted; therefore, overload must be avoided. Monitoring of the serum potassium is advisable for several hours after administration of the salt. For delirium or convulsions, intravenous administration of diazepam is indicated.

In pediatric patients, the estimated amount of ibuprofen ingested per body weight may be helpful to predict the potential for development of toxicity although each case must be evaluated. Ingestion of less than 100 mg/kg is unlikely to produce toxicity. Pediatric patients ingesting 100 to 200 mg/kg may be managed with induced emesis and a minimal observation time of at least four hours. Pediatric patients ingesting 200 to 400 mg/kg of ibuprofen should have immediate gastric emptying and at least four hours observation. Pediatric patients ingesting greater than 400 mg/kg require immediate medical referral, careful observation and appropriate supportive therapy. Induced emesis is not recommended in overdoses greater than 400 mg/kg because of the risk for convulsions and the potential for aspiration of gastric contents.

In adult patients, the dose reportedly ingested does not appear to be predictive of toxicity. The need for referral and follow-up must be judged by the circumstances at the time of the overdose ingestion. Symptomatic adults should be carefully evaluated, observed and supported.

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Examples of Ibuprofen Overdose

A 41-year-old man with multiple medical problems, including long-term renal insufficiency, developed near-fatal acute renal failure after ingestion of a massive dose (36 g) of ibuprofen. He required dialysis for several months, at which point his renal function improved.

In children, ibuprofen overdoses less than 100 mg/kg are unlikely to produce toxicity. In adults, the dose of ibuprofen reportedly ingested does not appear to be predictive of toxicity.

With electrolyte replacement and other intensive measures, a 21-month-old child recovered within 5 days after accidental ingestion of 8 g of ibuprofen. A 2-year-old child who ingested approximately 8 g of ibuprofen was treated with activated charcoal, developed metabolic acidosis and acute renal insufficiency, and recovered within 72 hours. A 6-year-old child became comatose after ingesting 6 g of ibuprofen. He was treated with gastric lavage, charcoal, and various supportive measures and recovered within 24 hours.

Examples of Pseudoephedrine Overdose

Hypertensive crisis (blood pressure 200/160 mmHg) was reported in a 23-year-old man after ingestion of 840 mg pseudoephedrine (in Trinalin tablets; also containing azatadine). The patient presented with severe headache, dizziness, diaphoresis, and epigastric pain. His hypertension was treated effectively with intravenous labetalol.

In a study to determine the toxicity of pseudoephedrine in children 2 to 6 years of age, 22% of 101 exposures to doses ranging from 30 to 180 mg were associated with drowsiness, and 7% were associated with mild hyperactivity. The symptoms were mild, and the children were treated with fluids and observation. Of 39 exposures to doses above 180 mg, 15% were associated with drowsiness and 13% were associated with mild hyperactivity.

Hypertension was reported in an 8-week-old infant after administration of pseudoephedrine 7.5 mg four times daily orally and phenylephrine 1/4% intranasally four times daily for 7 days. The infant's blood pressure normalized after discontinuation of the decongestants and remained normal at follow-up.

A 2-year-old boy was overdosed with a non-prescription cough and cold preparation containing 7.5 mg dextromethorphan and 15 mg pseudoephedrine per 5 mL. After receiving three doses of 1.5 teaspoonfuls spaced 6 hours apart, he developed hyperexcitability, hyperirritability, agitation, incoherent babbling, and difficulty maintaining his balance. On examination, the patient exhibited hyperactivity, ataxia, dilated pupils, and tachycardia (180 beats per minute). His status normalized over a period of 4 hours.

A 3-year-old girl experienced visual hallucinations after administration of a non-prescription decongestant containing pseudoephedrine. The child had inadvertently been given 20 mg/kg of pseudoephedrine administered in two doses over the previous 12 hours. A 5-year-old boy suffered from severe hallucinations beginning 5 hours after drinking 60 mL of syrup containing pseudoephedrine

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

and triprolidine (Actifed).

Pseudoephedrine overdose may precipitate psychosis in individuals with underlying psychiatric disorders.

A 27-year-old man with a history of bipolar affective disorders experienced an episode of acute paranoid psychosis after chronic abuse of Actifed syrup (pseudoephedrine and triprolidine). The patient had abused Actifed for several years, taking one to two bottles on weekends. Approximately 4 days prior to onset of visual and auditory hallucinations and paranoia, he had increased the amount to two bottles per day. His hallucinations disappeared within 1 day after discontinuation of Actifed.

A mixed bipolar psychotic disorder was precipitated by a large dose of pseudoephedrine in a 13-year-old girl with a familial predisposition to psychotic disorders. The patient took 8 tablets of 60 mg pseudoephedrine in one afternoon. She was hospitalized for psychiatric treatment and was discharged after 2 weeks. She had another psychotic episode 7 months later, without exposure to pseudoephedrine.

A 19-month-old girl who ingested approximately 600 mg of pseudoephedrine experienced a generalized tonic clonic seizure.

Examples of Ibuprofen/Pseudoephedrine Hydrochloride Combination Products Overdose

In seven of eight reports of overdose with an ibuprofen/pseudoephedrine hydrochloride combination, the patients recovered without hospitalisation. A 17-year-old woman ingested eight tablets of ibuprofen/pseudoephedrine hydrochloride combination plus 24 to 30 tablets of extra-strength Tylenol. She was treated with acetylcysteine solution (Mucomyst) and charcoal and was discharged from the hospital after a 2-day stay.

6. Dosage Forms, Strengths, Composition and Packaging

Table – Dosage Forms, Strengths, and Composition - Advil Cold And Sinus and Advil Cold And Sinus Daytime

Description

Advil Cold And Sinus and Advil Cold And Sinus Daytime Caplets are beige, sugar-coated tablets.

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Advil Cold And Sinus are available in blister packages of 10 and 20 caplets, and bottles of 40, 72, 102 caplets.

Advil Cold And Sinus Daytime caplets are available in blister packages of 12* and 24** caplets.

*Blister package of 12 caplets of Advil Cold And Sinus Daytime is available in combination with a blister package of 6 caplets of Advil Cold And Sinus Nighttime.

**Blister package of 24 caplets of Advil Cold And Sinus Daytime is available in combination with a blister package of 12 caplets of Advil Cold And Sinus Nighttime.

Table – Dosage Forms, Strengths, and Composition - Advil Cold & Sinus Liqui-Gels

Description

Advil Cold & Sinus Liqui-Gels are light-gold liquid-filled gelatin capsules. It is printed with "Advil" above “C&S” in black ink on one side. Available in blister packages of 20 capsules and bottles of 40 capsules.

Table – Dosage Forms, Strengths, and Composition - Advil Cold & Sinus Extra Strength Liqui-Gels

Description

Advil Cold & Sinus Extra Strength Liqui-Gels are clear orange liquid-filled gelatin capsules. It is printed with "Advil" above “C&S ES” in black ink on one side. Available in blister packages of 16 capsules and

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

bottles of 32 capsules.

Table – Dosage Forms, Strengths, and Composition - Children’s Advil Cold

Description

Children's Advil Cold is a translucent, purple, grape-flavoured suspension. Available in plastic bottles of 120 mL.

7. Warnings and Precautions

Please see 3 Serious Warnings and Precautions Box.

General

To minimize the potential risk for an adverse event, the lowest effective dose should be used for the shortest possible duration.

As with other anti-inflammatory drugs, ibuprofen may mask the usual signs of infection.

If nervousness, dizziness, or sleeplessness occurs, use of Advil Cold & Sinus products or Children’s Advil Cold should be discontinued and a physician should be consulted. Advil Cold & Sinus should not be used for more than 3 days for fever or 5 days for cold symptoms/pain. Children’s Advil Cold should not be used if fever worsens or persists for more than 3 days.

In case of an overdose, medical help or a poison control centre should be contacted immediately. Prompt medical attention is critical, even in the absence of signs or symptoms.

Pseudoephedrine content of this product may result in a positive reaction during antidoping control tests.

Carcinogenesis and Mutagenesis

Not applicable.

Cardiovascular

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Use of ibuprofen may precipitate congestive heart failure in patients with marginal cardiac function, elevated blood pressure, peripheral arterial disease and palpitations.

Clinical trial and epidemiological data suggest that the use of ibuprofen, particularly at high doses (2,400 mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g., ≤ 1200 mg daily) is associated with an increased risk of myocardial infarction.

Long term continuous use may increase the risk of heart attack or stroke.

Advil Cold & Sinus products and Children’s Advil Cold should be used with caution in hypertensive patients because of the possible pressor effect of pseudoephedrine. Pseudoephedrine has been shown to increase blood pressure in normotensive adults and in patients with hypertension.

Pseudoephedrine treatment may increase heart rate and can cause arrhythmia. Asymptomatic, multifocal premature ventricular contractions (PVCs) were reported with the use of Actifed (a combination of pseudoephedrine with an antihistamine, triprolidine), two tablets every 4 hours around the clock, for several days to treat nasal congestion. The PVCs disappeared within a few days after discontinuation of the medication.

There have been reports of acute systemic vasoconstrictive events with pseudoephedrine.

Significant examples include:

• Acute Coronary Syndrome (ACS): Symptoms include sudden chest pain, tightness, heavy sweating and dyspnoea at rest.
• Posterior reversible encephalopathy (PRES)/reversible cerebral vasoconstriction syndrome (RCVS): Symptoms included sudden onset of severe headache, nausea, vomiting, and visual disturbances. Most cases improved or resolved within a few days following appropriate treatment.

Pseudoephedrine should be discontinued immediately and medical advice sought if any signs/symptoms of vasoconstrictive events develop.

Dependence, Tolerance and/or Abuse Liability

Pseudoephedrine has the potential to cause drug dependency and withdrawal effects. Reportedly, a woman with a history of depression experienced a stimulatory effect from the use of 50 to 300 mL of Actifed (pseudoephedrine and triprolidine) daily (the recommended dose is 30 mL per day). A 37-year-old woman admitted to taking 100 to 150 30-mg pseudoephedrine tablets daily. She had gradually increased the daily dose over the previous 5 years to counteract chronic fatigue, apathy, and depression. A previous attempt to discontinue use of the drug had produced visual hallucinations, severe fatigue, and depression. Slow withdrawal by 200 to 300 mg/day resulted in a return of depressive symptoms; thereafter, the dose was decreased more slowly, by 90 mg/day. The patient was later diagnosed as having a mixed character disorder and reactive depression.

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Ear/Nose/Throat

See 2 Contraindications.

Endocrine and Metabolism

Patients with thyroid disease should not take this drug. See 2 Contraindications .

The use of pseudoephedrine is associated with a risk of severe hypertension in patients with phaeochromocytoma. Consider the overall benefit-risk before using this product in patients with pheochromocytoma.

Fluid and Electrolyte Balance

Fluid retention and oedema have been observed in patients treated with ibuprofen. Therefore, as with many other nonsteroidal anti-inflammatory drugs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Advil Cold & Sinus or Children’s Advil Cold should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.

With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with B-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients who are at risk.

Gastrointestinal

See 2 Contraindications. Serious GI toxicity, such as peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal, can occur at any time, with or without symptoms in patients treated with NSAIDs including ibuprofen.

Minor upper GI problems, such as dyspepsia, are common, usually developing early in therapy. Physicians should remain alert for ulceration and bleeding in patients treated with non-steroidal anti-inflammatory drugs, even in the absence of previous GI tract symptoms.

In patients observed in clinical trials of such agents, symptomatic upper GI ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. The risk continues beyond one year and possibly increases. The incidence of these complications increases with increasing dose.

Advil Cold And Sinus, Advil Cold And Sinus Daytime, Advil Cold & Sinus Liqui-Gels, Advil Cold & Sinus Extra Strength Liqui-Gels or Children’s Advil Cold should be given under close medical supervision to patients prone to gastrointestinal tract irritation, particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn's disease. In these cases, the physician must weigh the benefits of treatment against the possible hazards.

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and instruct them to contact a physician immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding. Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients by checking their haemoglobin periodically and by being vigilant for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.

If ulceration is suspected or confirmed, or if GI bleeding occurs, Advil Cold & Sinus products or Children’s Advil Cold should be discontinued immediately, appropriate treatment instituted, and the patient monitored closely.

No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. A prior history of serious GI events and other factors such as excess alcohol intake, smoking, age, female gender and concomitant oral steroid and anticoagulant use have been associated with increased risk. Studies to date show that all NSAIDs can cause GI tract adverse events. Although existing data does not clearly identify differences in risk between various NSAIDs, this may be shown in the future.

There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of Advil Cold & Sinus or Children’s Advil Cold therapy when and if these adverse reactions appear.

Ischemic colitis has been reported in association with the use of pseudoephedrine. In four separate cases, perimenopausal women had ingested varying quantities of pseudoephedrine (60 mg or more daily) for treatment of upper respiratory disorders. All patients had taken pseudoephedrine within the week preceding symptom onset, and all patients presented with complaints of acute onset abdominal pain associated with fresh blood in the stool. Colonoscopy revealed in each case a segmental colitis characterized by oedematous, hyperaemic colonic mucosa, most often in the region of the splenic flexure, yet also extending upward to involve the transverse colon. Several occurrences of frank mucosal haemorrhage were observed. Biopsy samples of mucosa revealed acute inflammatory changes consistent with ischemic colitis. In each case, the patient recovered without further incident or recurrence after pseudoephedrine was discontinued. Pseudoephedrine should be discontinued immediately and medical advice sought if any signs/symptoms of ischemic colitis develop.

Genitourinary

Some NSAIDs are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, treatment with Advil Cold & Sinus or Children’s Advil Cold must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.

Hematologic

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NSAIDs inhibiting prostaglandin biosynthesis do interfere with platelet function to varying degrees; patients who may be adversely affected by such an action, such as those on anticoagulants or suffering from haemophilia or platelet disorders, should be carefully observed when ibuprofen is administered.

Numerous studies have shown that the concomitant use of NSAIDs and anti-coagulants increases the risk of bleeding. Concurrent therapy with warfarin requires close monitoring of the international normalized ratio (INR). Even with therapeutic INR monitoring, increased bleeding may occur. (See 9.4 Drug – Drug Interactions - Anticoagulants).

Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anaemia and agranulocytosis) associated with the use of non-steroidal anti-inflammatory drugs are rare but could occur with severe consequences.

Hepatic/Biliary/Pancreatic

As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver function tests (AST, ALT, alkaline phosphatase) may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis and liver necrosis have been reported with nonsteroidal anti-inflammatory drugs.

Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), this drug should be discontinued.

During long-term therapy, liver function tests should be monitored periodically. If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.

The frequency of acute liver injury among 625,307 people who received NSAIDs in England and Wales between 1987 and 1991, was examined. There were 311,716 patients who were prescribed ibuprofen. The incidence of acute liver injury among ibuprofen users was 1.6/100,000; this was the lowest incidence among the 8 NSAIDs studied and was significantly lower than the incidence among users of ketoprofen, piroxicam, fenbufen, or sulindac. For NSAID users as a group, the only factors that had an independent effect on the occurrence of acute liver injury were the simultaneous use of hepatotoxic medication or the presence of rheumatoid arthritis. Based on these data, the short-term use of ibuprofen as an analgesic/antipyretic should not be of concern regarding the development of liver disease.

Immune

Patients with complete or partial syndrome of nasal polyps, rhinitis or other allergic manifestations should not use ASA or other anti-inflammatory agents. Fatal anaphylactoid reactions have occurred in such individuals even if they have taken NSAIDs in the past without any adverse effects (See 2 Contraindications).

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In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissue diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.

Monitoring and Laboratory Tests - Pregnancy

If Advil products are administered in the middle (approximately 20 weeks) to the end of the second trimester, it is recommended that pregnant women be closely monitored for amniotic fluid volume since these products may result in reduction of amniotic fluid volume and even oligohydramnios (see 7 Warnings and Precautions - 7.1.1 Pregnancy). Advil products are contraindicated for use in the third trimester of pregnancy.

Neurologic

Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of ibuprofen. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

There are published literature reports of psychosis and other psychiatric disturbances following pseudoephedrine administration, hence pseudoephedrine should be used with caution.

High plasma concentrations of phenylalanine in individuals with phenylketonuria may exacerbate the CNS effects of pseudoephedrine.

Ophthalmologic

Blurred and/or diminished vision has been reported with the use of ibuprofen and other non-steroidal anti-inflammatory drugs. If such symptoms develop this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.

Patients with glaucoma should be closely monitored.

Peri-Operative Considerations

See 2 Contraindications. In general, NSAIDs are discontinued prior to surgeries to decrease the risk of post-operative bleeding.

Use this product with caution in patients planning surgery. Acute perioperative hypertension may occur if volatile halogenated anesthetics are used simultaneously with indirect sympathomimetic agents. It is recommended that pseudoephedrine treatment be stopped 24 hours before anesthesia.

Psychiatric

See 7 Warnings and Precautions - Neurologic.

Renal

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Long term administration of nonsteroidal anti-inflammatory drugs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pre-treatment state.

Ibuprofen and its metabolites are eliminated primarily by the kidneys; therefore, the drug should be used with great caution in patients with impaired renal function. In these cases, utilisation of lower doses of Advil Cold & Sinus products or Children’s Advil Cold should be considered, and patients carefully monitored.

During long-term therapy kidney function should be monitored periodically.

Pseudoephedrine and its active metabolite are excreted chiefly via the kidneys. Therefore, dosage should be adjusted in patients with impaired kidney function. Myoclonic jerking and bizarre behaviour were reported in a haemodialysis patient with end-stage renal failure after taking 60 mg of pseudoephedrine four times daily for 12 days to treat nasal congestion.

Respiratory

Patients with asthma should not use ASA or other nonsteroidal anti-inflammatory agents. Fatal anaphylactoid reactions have occurred in such individuals even if they have taken NSAIDs in the past without any adverse effects (See 2 Contraindications).

Sensitivity/Resistance

Patients sensitive to any one of the nonsteroidal anti-inflammatory drugs may be sensitive to any of the other NSAIDs also.

Skin

Pseudoephedrine may induce non-pigmenting, fixed-type skin eruptions, which are typically indurated, erythematous, pruritic, tender, and oedematous. The reaction tends to occur within 24 hours after administration of pseudoephedrine and to resolve 2 to 3 days after discontinuation.

In rare cases, serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme have been associated with the use of some NSAIDs. Because the rate of these reactions is low, they have usually been noted during post-marketing surveillance in patients taking other medications also associated with the potential development of these serious skin reactions. Thus, causality is NOT clear. These reactions are potentially life threatening but may be reversible if the causative agent is discontinued and appropriate treatment

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instituted. Patients should be advised that if they experience a skin rash, they should discontinue their NSAID and contact their physician for assessment and advice, including which additional therapies to discontinue.

7.1 Special Populations

7.1.1 Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo-fetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy.

Advil Cold & Sinus products are contraindicated for use during the third trimester of pregnancy because of risk of premature closure of the ductus arteriosus.

Because of the known effects of NSAIDs on the fetal cardiovascular system, use of ibuprofen during late pregnancy should be avoided. (see Oligohydramnios/Neonatal Renal Impairment below).

Caution should be exercised in prescribing Advil products to women who are trying to conceive, or during the first and second trimesters of pregnancy (see 16 Non-Clinical Toxicology).

In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-fetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. However, animal reproduction studies are not always predictive of human response. As with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia and delayed parturition occurred in rats.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including Advil products, at approximately 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some more severe cases, neonatal respiratory, musculoskeletal and renal problems (see 16 Non-Clinical Toxicology).

Published studies and post-marketing reports describe maternal NSAID use at approximately 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment, or failure. NSAIDs were shown to cause significant reduction in fetal urine production prior to reduction of amniotic fluid volume. There have also been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible, even after treatment discontinuation.

These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

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If, after careful consideration of alternative treatment options for pain management, NSAID treatment is necessary anywhere from the middle (onset approximately 20 weeks) to the end of the second trimester of pregnancy, it is recommended that the use be limited to the lowest effective dose and shortest duration possible.

Consider ultrasound monitoring of fetal well-being, including of amniotic fluid volume assessment if treatment with Advil products extends beyond 48 hours. It is recommended that NSAIDs treatment be discontinued if oligohydramnios occurs, followed by appropriate medical follow up.

Inform pregnant women not to use Advil products and other NSAIDs from the third trimester of pregnancy because of the risk of the premature closing of the fetal ductus arteriosus (see 2 CONTRAINDICATIONS). If treatment with Advil products is needed for a pregnant woman anywhere from the middle (onset approximately 20 weeks gestation) to the end of the second trimester of pregnancy, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours.

7.1.2 Breastfeeding

Use of Advil Cold & Sinus products should be avoided during breastfeeding.

Ibuprofen is excreted in breast milk in very low concentrations and is considered unlikely to affect the breast-fed infant adversely.

Pseudoephedrine is excreted into breast milk in small amounts but the effect of this on breast fed infants is unknown.

7.1.3 Pediatrics

Pediatrics (<12 years of age): No data for Advil Cold & Sinus products are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

Pediatrics (6 – 12 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Children’s Advil Cold in pediatric patients has been established. Therefore, Health Canada has authorized an indication for pediatric use.

Pediatrics (<6 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for Children’s Advil Cold for children under 6 years of age.

7.1.4 Geriatrics

Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from nonsteroidal anti-inflammatory drugs (NSAIDs): the incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. The chance of stomach bleeding is higher if you are: age 60 or older, have had stomach ulcers or bleeding problems, take a blood thinner or steroid drug, take with other drugs

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containing an NSAID like acetylsalicylic acid (ASA), ibuprofen, naproxen, or prescription anti-inflammatory drugs, have 3 or more alcoholic drinks every day while using this product. Most reports of fatal GI events are in this population. Older patients are also at risk of lower oesophageal ulceration and bleeding. There is also increased susceptibility to effects of sympathomimetic amines observed in elderly patients.

Advil Cold & Sinus products are not indicated for use in patients over 65 years of age.

8. Adverse Reactions

8.1 Adverse Reaction Overview

Serious adverse reactions occur uncommonly with Advil Cold & Sinus products. The most common reactions include heartburn, constipation, nausea, bloating, nervousness or sleeplessness.

Adverse events are more likely to occur with increasing dose and duration of use.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Safety Studies of Ibuprofen and Pseudoephedrine Combination

In patients with upper respiratory infections treated with either ibuprofen 200 mg plus pseudoephedrine 30 mg (n = 294), acetaminophen 500 mg (n = 296), or placebo (n = 146), the frequency of adverse events (mostly gastrointestinal and CNS symptoms) was similar among the three treatment groups.

In a placebo-controlled, double-blind clinical study of 58 subjects with rhinovirus infection, pseudoephedrine given alone or with ibuprofen was well-tolerated. Symptoms associated with sympathetic stimulation tended to be more frequent in subjects who were treated with pseudoephedrine (60 mg, either alone or with 200 mg ibuprofen) than in those who received placebo. The three treatment groups were similar in mean pulse rate and mean blood pressure.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Adverse Events in Clinical Studies of Children’s Advil Cold

Three studies of Children’s Advil Cold were conducted in a total of 156 children 2 to 11 years of age (mean age, 5.9 years). In one of the studies, 104 children took the medication for up to 7 days to treat symptoms of upper respiratory infection. The mean number of days of treatment was 4.8. The other two studies were single-dose pharmacokinetic studies. One child withdrew from the multiple-dose study because of episodes of feeling “shaky.” The symptom resolved after study medication was discontinued.

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In combined data from the three studies, the most frequently reported adverse events were somnolence (in seven children), vomiting (in three children), and otitis media (in three children) (Table 1). Only two adverse events were considered severe: somnolence in one child, which lasted for about 1 hour and was considered remotely related to study medication, and ear pain, which resolved within 2 days without treatment and was considered unrelated to study medication. All other adverse events were considered mild or moderate in intensity.

Two large-scale safety studies of ibuprofen examined the potential risk in children of several rare events that are related to the pharmacological action of NSAIDs: GI bleeding, acute renal failure, and anaphylaxis.

8.5 Post-Market Adverse Reactions

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Safety Studies of Ibuprofen - children

The Children’s Analgesic Medicine Project (CAMP) was a multicenter, all-comers, open-label, nonrandomized, prospective study comparing the safety of ibuprofen suspension with acetaminophen suspension in children with fever and/or pain. A total of 424 paediatricians enrolled children at 69 US clinics; 14,281 were <2 years of age and 15,863 were 2 to <12 years of age. Among children <2 years of age, fever, vomiting, diarrhoea, rhinitis, rash, and otitis media were the only adverse events with frequency >1% in either treatment group (ibuprofen or acetaminophen). Among children 2 years of age, the only adverse events with frequency >1% in either treatment group were rhinitis, pharyngitis, and otitis media. Adverse events were generally mild to moderate for both treatments within the two age groups. There were no serious adverse events, (no anaphylaxis, Reye syndrome, renal failure, or GI bleeding/perforation). The percentage of younger children with adverse events was slightly higher in the ibuprofen group (17.6% vs. 15.0%); similar results were seen in the older children (11.9% vs. 10.7%). The difference may have been due to the preference of physicians to treat the sicker children with ibuprofen. Overall, ibuprofen exhibited an adverse event profile similar to that of acetaminophen.

The Boston Fever Study was a randomized, double-blind study that assessed the risk of rare but serious adverse events after the use of ibuprofen suspension in febrile children between 6 months and 12 years of age. The study evaluated a total of 83,915 children enrolled by 1735 paediatricians, family physicians, and general practitioners in the United States. Children were randomly assigned to receive ibuprofen suspension 5 mg/kg (N = 27,948), ibuprofen suspension 10 mg/kg (N = 27,837), or acetaminophen suspension 12 mg/kg (N = 28,130). Medications were given every 4 to 6 hours, as needed, for a total of up to five doses per day. The study recorded hospitalisations for acute GI bleeding, acute renal failure, and anaphylaxis and monitored for the occurrence of Reye syndrome. In the entire population, the authors found no significant difference between ibuprofen- and acetaminophen-treated children in the observed risk of GI bleeding, acute renal failure, or anaphylaxis. No cases of Reye syndrome were seen.

Safety Studies of Ibuprofen - adults

The results of a double-blind, placebo-controlled study in healthy subjects (N = 1246) representative of a non-prescription analgesic user population indicate that ibuprofen at a dosage of 1200 mg/day for 10 consecutive days is well tolerated. The frequency of gastrointestinal adverse experiences was similar in the placebo and ibuprofen groups (16% with placebo vs. 19% with ibuprofen). The most frequent gastrointestinal adverse experiences (those reported by ≥ 1% of the subjects) were dyspepsia, abdominal pain, nausea, diarrhoea, flatulence, and constipation. There was no difference between the two groups in the proportion discontinuing treatment because of gastrointestinal adverse events. Seventeen subjects (1.4%) had positive occult blood tests: the frequency was comparable for the two treatments.

In two multitrial analyses, a meta-analysis, and a literature review, ibuprofen had a low incidence of

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gastrointestinal drug reactions, comparable with that of acetaminophen and placebo. In epidemiological studies, ibuprofen has consistently exhibited the lowest relative risk of severe gastrointestinal complications compared with other NSAIDs and acetylsalicylic acid. No symptom or syndrome emerged in the trials that was not predicted from the drug’s pharmacology or could not have been anticipated based on ibuprofen’s extensive use as an analgesic/antipyretic in adults.

Garcia-Rodriguez reported on the frequency of acute liver injury among 625,307 people who received NSAIDs in England and Wales between 1987 and 1991, of whom 311,716 were prescribed ibuprofen. The incidence of acute liver injury among ibuprofen users was 1.6/100,000. This was the lowest incidence among the eight NSAIDs studied and was significantly lower than the incidence among users of ketoprofen, piroxicam, fenbufen, or sulindac. For NSAID users as a group, the only factors that had an independent effect on the occurrence of acute liver injury were simultaneous use of hepatotoxic medication and the presence of rheumatoid arthritis.

Adverse Events with Doses of Ibuprofen ≥ 1200 mg/day

The following adverse events have been noted in patients treated with prescription doses

(≥ 1200 mg/day).

Gastrointestinal

In clinical trials of NSAIDs, symptomatic upper GI ulcers, gross bleeding, or perforation occurred in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for 1 year. The risk continues beyond 1 year. The incidence of GI complications increases with increasing dose.

Incidence 3-9%: nausea, epigastric pain, heartburn. Incidence 1-3%: diarrhoea, abdominal distress, nausea and vomiting, indigestion, constipation, abdominal cramps or pain, fullness of the gastrointestinal tract (bloating or flatulence). Incidence <1%: gastric or duodenal ulcer with bleeding and/or perforation, gastrointestinal haemorrhage, melena, hepatitis, jaundice, abnormal liver function (SGOT, serum bilirubin and alkaline phosphatase).

Allergic

Incidence <1%: anaphylaxis (see 2 Contraindications). Causal relationship unknown: fever, serum sickness, lupus erythematosus.

Central Nervous System

Incidence 3-9%: dizziness. Incidence 1-3%: headache, nervousness. Incidence <1%: depression, insomnia. Causal relationship unknown: paraesthesias, hallucinations, abnormal dreams.

Aseptic meningitis and meningoencephalitis, in one case accompanied by eosinophilia in the cerebrospinal fluid, have been reported in patients who took ibuprofen intermittently and did not have any connective tissue disease.

Dermatologic

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Incidence 3-9%: rash (including maculopapular type). Incidence 1-3%: pruritus. Incidence <1%: vesiculobullous eruptions, urticaria, erythema multiforma. Causal relationship unknown: alopecia, Stevens-Johnson syndrome.

Cardiovascular

Incidence <1%: congestive heart failure in patients with marginal cardiac function, elevated blood pressure, palpitations. Causal relationship unknown: arrhythmias (sinus tachycardia, sinus bradycardia, palpitations).

Special Senses

Incidence 1-3%: tinnitus. Incidence <1%: amblyopia (blurred and/or diminished vision, scotomata, and/or changes in colour vision). Any patient with eye complaints during ibuprofen therapy should have an ophthalmological examination. Causal relationship unknown: conjunctivitis, diplopia, optic neuritis.

Haematologic

Incidence <1%: leukopenia, decreases in haemoglobin and haematocrit. Causal relationship unknown: haemolytic anaemia, thrombocytopenia, granulocytopenia, bleeding episodes (e.g., purpura, epistaxis, haematuria, menorrhagia).

Hepatic

Liver enzyme elevations may occur in up to 15% of patients treated with ibuprofen.

Renal

Acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome have been reported. Renal papillary necrosis has been reported. Causal relationship unknown: decreased creatinine clearance, polyuria, azotemia.

Endocrine

Causal relationship unknown: gynecomastia, hypoglycaemic reaction. Menstrual delays of up to 2 weeks and dysfunctional uterine bleeding occurred in nine patients taking ibuprofen, 400 mg t.i.d., for three days before menses.

Metabolic

Incidence 1-3%: decreased appetite, oedema, fluid retention.

Spontaneously Reported Adverse Events for Ibuprofen/Pseudoephedrine Products

Since the inception of marketing of combination ibuprofen/pseudoephedrine products, more than 3 billion doses have been distributed in the United States alone. During the period from 1989 to 2000, 411 reports were received describing 699 adverse drug reactions world-wide for all marketed products containing ibuprofen and pseudoephedrine in combination. Fifty-three of the reports were associated

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with a serious outcome, usually hospitalisation. One death was reported; in the reporter’s opinion, the death was related to staphylococcal septicaemia and not to ibuprofen/ pseudoephedrine. Table 2 lists the events that were spontaneously reported three or more times, by body system and preferred term from a coding dictionary (COSTART in most cases; also MedDRA).

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Safety Data on Pseudoephedrine From Case Reports

Hyperthermia

A 21-year-old man who was taking pseudoephedrine for weight loss died suddenly after receiving heat-phenol-inactivated typhoid vaccine and Japanese encephalitis vaccine. While on a 3-mile run 75 minutes after the inoculation, he collapsed and was found pulseless and apnoeic. He was in asystole, with a rectal temperature of 42.2°C. External pacing, cooling, and resuscitation efforts were unsuccessful. There was no evidence of urticaria, angioedema, heart failure, thrombosis, cerebral oedema, or petechial haemorrhage. The sympathomimetic effects of pseudoephedrine may have decreased the cooling ability of the body and increased susceptibility to heat-related adverse effects. The combined pyrogenic effects of the vaccines, exercise, mild obesity, and an impaired thermoregulatory system may have contributed to the patient's death.

Cardiovascular Adverse Reactions

Hypertension and loss of consciousness were reported in a 17-year-old man within 30 minutes after ingestion of one tablet of pseudoephedrine 60 mg. Blood pressure on admission was 170/110 mmHg, pulse was 124 beats per minute, and the patient was unresponsive to painful stimuli. Approximately 1 hour after ingestion of pseudoephedrine, the patient awoke spontaneously. Blood pressure was 124/80

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mmHg; pulse was 96 beats per minute. Pseudoephedrine may have induced a state of relative cerebral ischemia secondary to carotid vasoconstriction.

Postural hypotension was reported in a 28-year-old male airplane pilot after administration of pseudoephedrine 60 mg three times daily for 2 days. Physical examination revealed a supine blood pressure of 115/74 mmHg, which fell to 96/60 upon standing and was associated with dizziness lasting 10 to 15 seconds. Symptoms disappeared after discontinuation of pseudoephedrine and recurred upon rechallenge.

Pseudoephedrine was reported to cause coronary artery spasm and myocardial infarction in a 28-year-old man. The patient took 30 mg pseudoephedrine for rhinitis and experienced chest pressure. The next night he took an additional 60 mg and had crushing chest pressure. An electrocardiogram showed ST-segment elevation consistent with a myocardial infarction, and cardiac enzymes were elevated. The pain and electrocardiographic changes resolved after administration of sublingual nitroglycerin.

Dermatologic Adverse Reactions

Brownstein reported two cases of fixed-type skin eruptions after use of Actifed, a combination of pseudoephedrine with an antihistamine, triprolidine. The rashes subsided within a few days after the medication was discontinued but reappeared after the patients again ingested Actifed. One of the two patients was challenged three times with 50-mg doses of pseudoephedrine. Each time, the rash recurred at the same sites. A fixed drug eruption was described in a 48-year-old woman on two occasions after administration of pseudoephedrine. Indurated erythematous plaques developed on the right upper eyelid, elbows, antecubital fossae, axillae, and lower legs. The lesions were mildly pruritic. Discontinuance of pseudoephedrine and corticosteroid therapy resulted in clearing of the eruption on both occasions. Two similar cases of pseudoephedrine-induced fixed drug eruptions have been reported.

In multiple separate episodes over the course of 19 years, a man developed intense pruritus of the fingers about 12 hours after ingesting pseudoephedrine-containing products. This was followed by severe redness, swelling, heat, and white papules on the fingers. The swelling subsided after 7 days and was followed by desquamation lasting about 2 weeks.

After ingesting medication containing triprolidine plus 60 mg pseudoephedrine, a 10-year-old boy developed an oedematous, erythematous plaque. The lesion cleared within 2 weeks and reappeared at the same site after rechallenge with 30 mg pseudoephedrine.

Pseudoephedrine was associated with pseudo-scarlatina in a 32-year-old woman. The reaction recurred after rechallenge with pseudoephedrine.

Other Types of Adverse Reactions

Severe agitation, screaming, and confusion occurred in a 10-month-old infant with phenylketonuria after administration of pseudoephedrine 15 mg every 6 hours for treatment of acute otitis media. Symptoms were noted within 1 hour after the first dose and recurred after each dose for two subsequent doses. After discontinuation of pseudoephedrine, no further episodes occurred. The

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patient's plasma concentration of phenylalanine, which had previously ranged from 2 to 7 mg/dL, increased to 12 mg/dL during the illness.

An 18-year-old woman developed symptoms presenting as recurrent toxic shock syndrome after ingesting pseudoephedrine-containing cold preparations and after a challenge with 60 mg pseudoephedrine. She remained symptom-free for 1 year, during which she avoided pseudoephedrine-containing medications. When she inadvertently used a cough syrup containing pseudoephedrine, she again developed toxic shock symptoms.

Additional Post-market Adverse Reactions

The following reactions have been reported in post-market surveillance related to the active ingredients and are organized by System Organ Class and preferred term and where available the occurrence:

common (>1/100 to 1/10)

uncommon (≥1/1,000 to <1/100)

rare (≥1/10,000 to <1/1,000)

very rare (<1/10,000)

not known (cannot be estimated from available data).

Adverse Reactions Observed With Ibuprofen

Adverse Reactions Observed With Pseudoephedrine hydrochloride

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9. Drug Interactions

9.1 Serious Drug Interactions

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9.2 Drug Interactions Overview

Advil Cold And Sinus, Advil Cold And Sinus Daytime, Advil Cold & Sinus Liqui-Gels, Advil Cold & Sinus Extra Strength Liqui-Gels or Children’s Advil Cold is not recommended for concomitant use with any other NSAIDs, including ASA and other ibuprofen. Documented or possible drug interactions with Advil Cold & Sinus products or Children’s Advil Cold include acetaminophen, digoxin, anticoagulants, oral antidiabetic agents and insulin, antihypertensives, diuretics, methotrexate, lithium, and other protein-bound drugs.

9.3 Drug-Behaviour Interactions

Avoid drinking alcohol while taking Advil Cold & Sinus products, as this may increase the risk of serious stomach bleeding. Avoid smoking while taking Advil Cold & Sinus or other NSAIDs.

9.4 Drug-Drug Interactions

The drugs listed in this section are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Acetaminophen

Although interactions have not been reported, concurrent use with Advil Cold & Sinus products or Children’s Advil Cold is not advisable: it may increase the risk of adverse renal effect.

Acetylsalicylic acid (ASA) or other NSAIDs

The use of Advil Cold & Sinus products or Children’s Advil Cold in addition to any other NSAID, including ASA, is not recommended due to the possibility of additive side effects. Animal studies show that acetylsalicylic acid given with NSAIDs, including ibuprofen, yields a net decrease in anti-inflammatory activity with lowered blood levels of the non-acetylsalicylic acid drug. Single-dose bioavailability

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studies in normal volunteers have failed to show an effect of acetylsalicylic acid on ibuprofen blood levels. Correlative clinical studies have not been conducted (See 2 Contraindications).

Acetylsalicylic acid (ASA) Low Dose

Ibuprofen can interfere with the anti-platelet effect of low-dose ASA (81 - 325 mg per day). Long-term daily use of ibuprofen may render ASA less effective when used for cardio-protection and stroke prevention. To minimize this interaction, regular users of ibuprofen and low-dose, immediate-release ASA should take the ibuprofen at least one hour after or 11 hours before the daily low-dose ASA. The use of delayed-release (e.g. enteric coated) ASA is not recommended when using ibuprofen regularly. Healthcare professionals should advise consumers and patients regarding the appropriate concomitant use of ibuprofen and ASA.

Aminoglycosides

Reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Antacids

A bioavailability study has shown that there was no interference with the absorption of ibuprofen when given in conjunction with an antacid containing aluminium hydroxide and magnesium hydroxide.

Anticoagulants

Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of GI adverse events such as ulceration and bleeding. Because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet function, concurrent therapy of ibuprofen with warfarin requires close monitoring to be certain that no change in anticoagulant dosage is necessary. Several short-term controlled studies failed to show that ibuprofen significantly affected prothrombin time or a variety of other clotting factors when administered to individuals on coumarin-type anticoagulants. Nevertheless, the physician, should be cautious when administering Advil Cold & Sinus products or Children’s Advil Cold to patients on anticoagulants.

Antihypertensives

Prostaglandins are an important factor in cardiovascular homeostasis and inhibition of their synthesis by NSAIDs may interfere with circulatory control. NSAIDs may elevate blood pressure in patients receiving antihypertensive medication. Two meta-analyses have observed this relationship for NSAIDs as a class and for certain NSAIDs in particular, but ibuprofen did not significantly affect blood pressure in either meta-analysis. Consistent with this lack of effect, a study by Davies et al showed that ibuprofen 1600 mg/day for 14 days did not attenuate the antihypertensive effect of two β-adrenergic blockers. Houston et al showed no effect of three weeks’ therapy with ibuprofen on the antihypertensive efficacy of verapamil, but it is not known whether this lack of interaction extends to other classes of calcium channel blockers.

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When renal perfusion pressure is reduced both prostaglandins and angiotensin II are important mediators of renal autoregulation. As a class, the combination of an NSAID and angiotensin converting enzyme inhibitor theoretically may have the potential to decrease renal function. One study found a clinically significant decrease in renal function in 4 of 17 patients treated with hydrochlorothiazide and fosinopril who received ibuprofen 2400 mg/day for one month. In contrast, Minuz found no effect on the antihypertensive effect of enalapril or on plasma renin or aldosterone following two days’ treatment with ibuprofen 1200 mg/day.

The relationship of ibuprofen and antihypertensives is clearly not well defined. The benefits of concomitant medication should be analysed and compared to the potential risks before being prescribed. If ibuprofen is being recommended for long-term use, then periodic monitoring of blood pressure may be useful. Blood pressure monitoring is not necessary if ibuprofen is being recommended for short-term use as an analgesic.

Pseudoephedrine may antagonise the effect of certain classes of antihypertensives (e.g. beta-blockers, methyl-dopa, reserpine, debrisoquine, guanethidine).

Cough-cold/allergy Medications

The use of other decongestants, cough and cold medications, allergy medications or medications containing pseudoephedrine or ibuprofen should be avoided as it can increase the risk of serious side effects and overdose.

Cyclosporin

There is an increased risk of nephrotoxicity.

CYP2C9 Inhibitors

Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase the exposure to ibuprofen (CYP2C9 substrate). In a study with voriconazole and fluconazole (CYP2C9 inhibitors), an increased S(+)-ibuprofen total exposure (AUC) by approximately 80 to 100% has been shown. Reduction of the ibuprofen dose should be considered when potent CYP2C9 inhibitors are administered concomitantly, particularly when high-dose ibuprofen is administered with either voriconazole or fluconazole.

Digoxin

Ibuprofen has been shown to increase serum digoxin concentration. Increased monitoring and dosage adjustments of digitalis glycoside may be necessary during and following concurrent ibuprofen therapy.

Diuretics

Clinical studies, as well as random observations, have shown that ibuprofen can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of

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renal prostaglandin synthesis. During concomitant therapy with ibuprofen, the patient should be observed closely for signs of renal failure as well as to assure diuretic efficacy.

Glucocorticoids

Some studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of GI adverse events such as ulceration and bleeding. This is especially the case in older (> 65 years of age) individuals.

H-2 antagonists

In studies with human volunteers, coadministration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations.

Halogenated anaesthetics

Pseudoephedrine may interact with halogenated anaesthetics.

Hypoglycaemic Agents

Ibuprofen may increase hypoglycaemic effects of oral antidiabetic agents and insulin.

Lithium

Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in a study of eleven normal volunteers. The mean minimum lithium concentration increased 15% and the renal clearance of lithium was decreased by 19% during this period of concomitant drug administration. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when ibuprofen and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate

Ibuprofen as well as other NSAIDs has been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that ibuprofen could enhance the toxicity of methotrexate. Caution should be used when ibuprofen is administered concomitantly with methotrexate.

Monoamine Oxidase Inhibitors

Advil Cold & Sinus products or Children’s Advil Cold should not be used concomitantly with MAO inhibitors or for 14 days after stopping the MAOI drug. MAO inhibitors are prescribed for treatment of depression, psychiatric or emotional conditions, or Parkinson’s disease. Hypertensive crisis and other serious adverse reactions have been reported in patients using pseudoephedrine or other sympathomimetic drugs such as ephedrine in combination with or shortly after discontinuing MAO inhibitors (See 2 Contraindications).

Other Drugs

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Advil Cold & Sinus products or Children’s Advil Cold should be used with caution when other drugs, also having a high affinity for protein binding sites, are used concurrently. However, while ibuprofen binds extensively to plasma proteins, interactions with other protein-bound drugs occur rarely. Caution should be used when taking Advil Cold & Sinus products or Children’s Advil Cold in conjunction with probenecid, thyroxine, cyclosporine, antibiotics (e.g. levofloxacin), phenytoin, corticosteroids or benzodiazepines.

Oxazolidinone class of antibiotics

The oxazolidinone class of antibiotics (including linezolid) are known to cause a dose-related inhibition of monoamine oxidase. Therefore, they should not be taken with pseudoephedrine as there is a potential to cause hypertensive crisis.

Quinolones

NSAIDs can increase the risk of convulsion associated with quinolone antibiotics.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Studies report an increased risk of gastrointestinal (GI) ulceration and bleeding when Ibuprofen as well as other NSAIDs are taken concomitantly with selective serotonin reuptake inhibitors (SSRIs) than when either class of drugs is taken alone (See 7 Warnings and Precautions - Gastrointestinal).

Sympathomimetics

Concomitant use of pseudoephedrine with sympathomimetic agents (such as decongestants, tricyclic antidepressants, appetite suppressants and amphetamine-like medicines) may occasionally cause a rise in blood pressure.

Vasoconstrictive agents

Concomitant administration of pseudoephedrine with vasoconstrictive agents including ergot derivatives (such as bromocriptine, cabergoline, dihydroergotamine) may cause an increased risk of ergotism.

Zidovudine

There is an increased risk of hemarthroses and haematoma in HIV (+) haemophiliacs.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbs have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

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10. Clinical Pharmacology

10.1 Mechanism of Action

Ibuprofen

Like other nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen is an analgesic, antipyretic, and anti-inflammatory medication. The principal mechanism of action of ibuprofen and other NSAIDs is inhibition of prostaglandin biosynthesis. Prostaglandins contribute to fever, pain, and inflammation by sensitizing tissues to pain- and inflammation-producing mediators such as histamine, 5-hydroxytryptamine, and kinins. The committed step in prostaglandin biosynthesis is catalyzed by prostaglandin endoperoxide synthase, also known as cyclooxygenase. NSAIDs decrease prostaglandin biosynthesis by inhibiting cyclooxygenase.

A recent study confirmed that ibuprofen 400 mg provided a significantly faster onset of relief as measured by first perceptible relief, meaningful relief, percent attaining complete relief, and superior overall analgesic efficacy compared to acetaminophen 1000 mg for relief of episodic tension-type headache.

Pseudoephedrine Hydrochloride

Pseudoephedrine acts directly on both alpha- and, to a lesser degree, beta-adrenergic receptors. It is believed that alpha-adrenergic effects result from inhibition of the production of cyclic adenosine-3',5'-monophosphate (AMP) by inhibition of the enzyme adenyl cyclase, whereas beta-adrenergic effects result from stimulation of adenyl cyclase activity. Like ephedrine, pseudoephedrine also acts indirectly by releasing norepinephrine from its storage sites.

Pseudoephedrine acts directly on alpha-adrenergic receptors in the mucosa of the respiratory tract, producing vasoconstriction that results in shrinkage of swollen nasal mucous membranes, reduction of tissue hyperaemia, oedema, and nasal congestion, and, thereby, an increase in nasal airway patency. Drainage of sinus secretions is increased, and obstructed eustachian ostia may be opened.

10.2 Pharmacodynamics

Ibuprofen

Animal Pharmacology

Cyclooxygenase inhibitors such as ibuprofen and other NSAIDs reduce thromboxane A2 production and release, thereby decreasing platelet aggregation. Like many other NSAIDs, ibuprofen inhibits platelet aggregation, as demonstrated in vivo by prevention of platelet disposition in aortopulmonary arterial bypass grafts in dogs. The drug’s protective action against pulmonary embolism in rabbits injected intravenously with arachidonic acid may also relate to inhibition of platelet aggregation. The decreased platelet aggregation may be due in part to a reduction in membrane fluidity.

The penetration of ibuprofen into rabbit and rat foetuses was investigated. Rabbits and rats in late pregnancy were given single oral doses of 60 and 20 mg/kg respectively of C¹⁴-labeled ibuprofen.

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Rabbits were killed 3 hours after dosing, and rats were killed 1.5 hours after dosing. Blood samples were collected from the mothers and foetuses. The concentrations of radioactively labelled material were similar in maternal and foetal blood, indicating that ibuprofen and its metabolites readily crossed the placenta and entered the foetal circulation.

Human Pharmacology

In healthy volunteers, platelet aggregation decreased significantly at a dosage of 1800 mg per day of ibuprofen given over a period of 28 days. Ibuprofen influenced ADP-induced aggregation to a lesser extent than collagen-induced aggregation. Platelet aggregation induced by recalcification of citrated platelet-rich plasma (a thrombin-induced reaction) was not influenced by ibuprofen treatment. Likewise, ibuprofen did not affect whole blood clotting time on recalcification or prothrombin time. Bleeding time measured 2 hours after administration of ibuprofen showed a significant, dose-related increase.

Pseudoephedrine Hydrochloride

Animal Pharmacology

In dogs, pseudoephedrine acts as a vasopressor and vasoconstrictor with positive inotropic and chronotropic effects. In all these effects, pseudoephedrine is less potent than ephedrine. The bronchodilating potencies of pseudoephedrine and ephedrine in anaesthetized dogs are approximately equal, but pseudoephedrine produces a greater degree of nasal decongestion with less cardiovascular involvement than ephedrine. Pseudoephedrine increases plasma corticosterone levels and produces hyperglycemia in mice.

Human Pharmacology

Pseudoephedrine at doses up to 180 mg is approximately one-fourth as potent as ephedrine in producing tachycardia and increased systolic blood pressure; diastolic pressure is unchanged. After a single dose of pseudoephedrine 180 mg immediate release, three divided doses of 60 mg, or a sustained-release 180-mg dose, increases in heart rate and diastolic blood pressure were noted. At doses from 60 mg to 240 mg, few changes in pulse rate were noted, and no abnormalities or ectopic beats were noted on an electrocardiogram; at 210 mg, changes in diastolic blood pressure were noted.

Single pseudoephedrine doses of 180 mg produced minor elevations in systolic blood pressure (about 7 mmHg), minor increases in heart rate (about 9 beats per minute), and no changes in diastolic blood pressure in healthy subjects. Single doses of 60 mg had minimal effects.

Clinical studies of the cardiovascular effects of pseudoephedrine in subjects with controlled hypertension have produced differing results. A single 60-mg dose of pseudoephedrine compared with placebo produced significant increases in mean systolic blood pressure and heart rate in 20 hypertensive subjects. Mean diastolic blood pressure and mean arterial pressure also increased, but not significantly. Beck et al found minimal increases in blood pressure and heart rate in patients with medically controlled hypertension treated with 120 mg sustained-release pseudoephedrine twice daily. In other studies, pseudoephedrine at standard doses had no significant effect on systolic or diastolic

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blood pressure. In subjects with phaeochromocytoma, pseudoephedrine increased blood pressure and plasma noradrenaline concentration.

In children 6 to 12 years of age given 30-mg and 60-mg doses of pseudoephedrine in a pharmacokinetic study, pulse rate increased significantly at 4 hours postdose, particularly after the 60 mg dose. No clinically important adverse effects on blood pressure or on the central nervous system were noted.

A dose-related increase in frequency of sinus arrhythmias was observed after treadmill exercise in healthy subjects receiving pseudoephedrine. The mean number of episodes of arrhythmia during recovery from exercise was 0.17, 2.17, and 4.33 in subjects pretreated with placebo, pseudoephedrine 60 mg, and pseudoephedrine 120 mg, respectively. Short-lived unifocal premature ventricular contractions were experienced by two subjects.

In an investigation of the effects on pseudoephedrine on uterine and foetal blood flow, 12 healthy, pregnant women between 26 and 40 weeks of gestation ingested a 60-mg dose of pseudoephedrine. Doppler blood flow measurements taken during the first 3 hours after drug ingestion showed no significant alterations in maternal or foetal circulation.

Pseudoephedrine at a dose of 180 mg was reported to produce no significant mood alterations or changes in subjective ratings of mental state. In a study of the effects of pseudoephedrine on day- and nighttime central nervous system activity, there was no evidence of impairment of daytime activity as measured by objective tests (critical flicker fusion, choice reaction time, simulated car tracking test, and Sternberg Memory Scanning Test) or subjective tests (analog rating scales). Improvements were seen in psychomotor function (choice reaction time) and information processing (critical flicker fusion). Detrimental effects on nighttime central nervous system activity indicative of sleep disturbances (electroencephalogram, Leeds Sleep Evaluation Questionnaire) were noted with pseudoephedrine at doses of 60 mg and 120 mg.

Pseudoephedrine administered as a single 60-mg dose or 120-mg dose or administered at 1–2 mg/kg had no significant effect on exercise performance. Pseudoephedrine at doses of 60 mg and 120 mg had no effect on the time required to reach 85% maximal predicted heart rate on a treadmill or to return to baseline heart rate; on blood pressure at rest, during exercise, or in the recovery period; or on post-exercise blood glucose and insulin levels.

The effect of pseudoephedrine as a bronchodilator is small at a 210-mg dose and is approximately one-half that of ephedrine. In a study of subjects with reversible airway obstruction, pseudoephedrine at 60 mg and 180 mg produced no significant bronchodilation.

10.3 Pharmacokinetics

Absorption

Ibuprofen

Ibuprofen is rapidly absorbed after oral administration. Serum concentrations reach a peak within 1 to 2 hours in adults and in children. Food decreases the rate but not the extent of ibuprofen absorption.

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Pseudoephedrine Hydrochloride

After oral administration, pseudoephedrine is readily and completely absorbed from the gastrointestinal tract, with no evidence of first-pass metabolism. After oral administration of syrups containing 60 mg or 120 mg of pseudoephedrine, peak plasma pseudoephedrine concentrations of 180 ng/mL to 422 ng/mL, respectively, were obtained at 1 to 2 hours.

In a study of five children aged 6 to 12 years receiving 2 mg/kg of pseudoephedrine up to a maximum dose of 60 mg, the peak concentration (Cmax) was 338 ng/mL, Tmax was 1.86 hours, and t_1/2 was 4.61 hours. More recently, Simons et al characterized the pharmacokinetics of pseudoephedrine in children with seasonal allergic rhinitis. The results are presented in Table 3.

In a study in 25 children 6 to 11 years of age, the absorption of pseudoephedrine from an Advil Cold And Sinus tablet (ibuprofen 200 mg/pseudoephedrine 30 mg) was found to be equivalent to the absorption of pseudoephedrine from a Sudafed tablet (pseudoephedrine 30 mg) (Table 4).

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Note: Values are means (SEM). AUC_L = AUC to last measurable concentration, AUC_I = AUC extrapolated to infinity.

The absorption rate of pseudoephedrine, as measured by its urinary excretion rate, is significantly increased by the concurrent administration of aluminium hydroxide gel, is decreased by kaolin, and is unaffected by sodium bicarbonate. Food appeared to delay absorption of pseudoephedrine from syrup formulations and controlled-release capsules but had no effect on absorption from a suspension.

Distribution

Ibuprofen

After oral administration, the volume of distribution of ibuprofen was 0.1–0.2 L/kg in adults and 0.18-0.22 L/kg in febrile children. At therapeutic concentrations, ibuprofen is extensively bound to whole human plasma and binds primarily to site II of purified albumin.

Pseudoephedrine Hydrochloride

The volume of distribution of pseudoephedrine ranged from 2.64 L/kg to 3.51 L/kg in single- and multiple-dose studies. Pseudoephedrine concentration-time data after oral administration are well described using a one body compartment model with first-order absorption and elimination. The approximate plasma clearance of pseudoephedrine is 0.44 L/h/kg.

Metabolism

Ibuprofen

Ibuprofen is a racemic mixture of R-(-) ibuprofen and S-(+) ibuprofen. R-(-) ibuprofen undergoes extensive (53% to 65%) enantiomeric conversion to S-(+) ibuprofen in humans. S-(+) ibuprofen is the pharmacologically active enantiomer.

The plasma half-life (t½) of ibuprofen in adults and children is 1.5 - 2.0 hours. There is no appreciable plasma accumulation of ibuprofen or its metabolites with repeated doses. Two major metabolites, 2-[4-(2-carboxypropyl)phenyl] propionic acid and 2-[4-(2-hydroxy-2-methyl)propyl] phenyl propionic acid, have been identified in plasma and in urine. Parent drug and metabolites are excreted primarily in the urine. Bile and faeces are relatively minor elimination routes. Approximately 80% of an ibuprofen dose is recovered in urine within 24 hours, primarily as carboxymetabolites and hydroxymetabolites, both conjugated and unconjugated.

Cytochrome P450 (CYP) 2C9 has been identified as the most important enzyme in the oxidative metabolism of R-(-) and S-(+) ibuprofen. Ibuprofen does not appear to induce the formation of drug-metabolizing enzymes in rats.

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There is no evidence of changes in metabolism or elimination of ibuprofen with advanced age. A pharmacokinetic evaluation of ibuprofen in subjects 65 to 78 years of age compared with young adult subjects (22 to 35 years of age) found no clinically significant difference in the pharmacokinetic profiles of ibuprofen for the two age groups. Furthermore, there was no statistically significant difference between the two age groups in the urinary excretion pattern of the drug and its major metabolites. The pharmacokinetic results for ibuprofen in children are similar to findings in adults.

Pseudoephedrine Hydrochloride

Less than 1% of pseudoephedrine is eliminated by hepatic metabolism. The major biotransformation of pseudoephedrine is N-demethylation to the active metabolite norpseudoephedrine.

Because pseudoephedrine is a weak base, with a pKa of 9.2, its half-life is dependent on urinary pH. The serum half-life increases as urine pH increases, varying from 1.9 hours at pH 5.6 to 21 hours at pH 7.8. At urine pH greater than 7.0, pseudoephedrine is extensively reabsorbed in the renal tubules, and therefore its excretion rate is dependent on urine flow rate. Higher flow rates decrease the intratubular drug concentration and the time for reabsorption, leading to greater renal clearance. When urine pH is acidic, renal reabsorption is negligible and urine flow does not influence clearance of the drug.

In a study in children in which the urine pH was 6.5, pseudoephedrine had a shorter half-life (3.1 hours) and faster clearance (9.2 to 10.3 mL/min/kg) than in studies of similar design in adults in which the urine pH was not controlled or reported. Fifty-six percent of the pseudoephedrine dose was recovered in the urine within 12 hours, and an additional 10% was recovered over the period from 12 to 24 hours.

The shorter terminal elimination half-life of pseudoephedrine in children may reflect greater renal tubular secretion or reabsorption in children than in adults. The faster clearance rate and smaller volume of distribution in children than in adults is probably due to the relatively lower lean body mass in children. Over the 30-mg to 60-mg dose range, the kinetics of pseudoephedrine in children were not dose dependent.

Elimination

Ibuprofen

Ibuprofen is rapidly excreted in breast milk. Thirty minutes after oral ingestion of 400 mg of ibuprofen, the concentration in breast milk was found to be 13 ng/mL. The milk:plasma ratio was 1:126, and the exposure of a suckling infant to ibuprofen was calculated to be approximately 0.0008% of the maternal dose. Studies in animals indicate that ibuprofen is transported across the placenta.

Pseudoephedrine Hydrochloride

Pseudoephedrine is excreted largely unchanged in urine, with 43% to 96% recovered in 24 hours. Norpseudoephedrine recovery from urine ranged from less than 1% to 6.2%.

Pseudoephedrine is presumed to cross the placenta and to enter the cerebrospinal fluid.

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

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Approximately 0.4% to 0.7% of an oral dose is excreted in breast milk over 24 hours. Pseudoephedrine levels two to three times higher in milk than in plasma have been reported. Adverse effects (irritability, excessive crying, disturbed sleeping patterns) were reported in a breast-fed infant whose mother had received pseudoephedrine. The symptoms resolved within 12 hours after discontinuation of pseudoephedrine.

11. Storage, Stability and Disposal

Temperature and Moisture:

Advil Cold And Sinus, Advil Cold And Sinus Daytime, Advil Cold & Sinus Liqui-Gels, Advil Cold & Sinus Extra Strength Liqui-Gels and Children’s Advil Cold should be stored in tightly closed containers at room temperature (15 to 30°C). Protect from moisture.

Others:

Keep in a safe place out of the reach and sight of children.

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substances

Proper name: Ibuprofen

Chemical name: α-methyl-4-(2-methylpropyl) benzeneacetic acid

Other names: p-isobutylhydratropic acid

2-(4-isobutylphenyl)-propionic acid

Molecular formula and molecular mass: C₁₃H₁₈0₂

206.28 daltons

Structural formula:

Physicochemical properties: White or almost white powder or crystals with a characteristic odour.

Solubility: Low solubility in water (<0.1 mg/mL), soluble 1 in 1.5 of alcohol, 1 in 1 of chloroform, 1 in 2 of ether, and 1 in 1.5 of acetone. Ibuprofen is also soluble in an aqueous solution of alkali hydroxides and carbonates.

pKa value: pKa = 4.43

Melting Point: 75-77°C

Proper name: Pseudoephedrine hydrochloride

Chemical name: {S-(R*, R*)-α -{1-(methylamino)ethyl} benzenemethanol hydrochloride

Other names (+)-Pseudoephedrine hydrochloride

Molecular Formula and molecular mass: C₁₀H₁₅NO ^XHCl

201.70 daltons

CH₃

COOH

CH₃

H₃C

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Structural Formula:

Physicochemical Properties: White powder or crystals

Solubility: Soluble in water, alcohol, and chloroform

pKa and pH values: pKa = 9.2, pH = 5.9 in an aqueous solution of 1 in 200

Melting Point: 180-186°C

14. Clinical Trials

14.1 Clinical Trials by Indication

Published studies have documented the efficacy of 200-mg and 400-mg doses of ibuprofen in treating mild to moderate pain, including sore throat pain, headache, and muscle aches in adults. The antipyretic efficacy of ibuprofen has been demonstrated in adults at doses of 200 and 400 mg and in children at doses of 5 to 10 mg/kg. Ibuprofen is effective in treating the pain of sore throat in children.

A randomized, double-blind, placebo-controlled study in 179 subjects with nasal congestion secondary to upper respiratory tract infection showed a statistically significant increase in total nasal airflow 2 hours after single oral doses of pseudoephedrine 60 mg or ibuprofen 400 mg plus pseudoephedrine 60 mg. Time-weighted sums of changes in nasal airflow relative to baseline were greater with both active treatments than with placebo (Table 5).

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

^a Pairwise comparisons. Additional pairwise comparisons showed no significant differences between the two active treatments (p = 0.524 for the first 4 hours postdose, 0.653 for the entire 6-hour period postdose).

Pseudoephedrine at a dose of 60 mg increases maximal nasal inspiratory flow rate and produces objective improvement in nasal airway resistance. A single 60-mg oral dose of pseudoephedrine produced marked nasal decongestant effects within 30 minutes of administration, lasting for at least 4 hours. In 40 subjects with nasal congestion associated with the common cold, two 60-mg doses of pseudoephedrine 4 hours apart produced no significant difference in maximum unilateral nasal airflow or total nasal air flow over a 7-hour period; however, minimum unilateral nasal air flow was significantly increased. A single 60-mg dose of pseudoephedrine administered to subjects with nasal congestion due to the common cold significantly increased total nasal minimum cross-sectional area and nasal volume measured by acoustic rhinometry. There was no significant change in nasal area as measured by active posterior rhinomanometry.

In a double-blind, randomized study, the decongestant activity of pseudoephedrine was dose related over the range of 30 to 60 mg, as measured by total nasal air flow (sum of left and right nares) in 112 subjects with nasal congestion associated with allergic rhinitis (Figure 1). At most time points postdose, the decongestant effect of the combination of ibuprofen 200 mg plus pseudoephedrine 30 mg was midway between that seen for pseudoephedrine 45 mg and 60 mg and greater than the decongestant effect of pseudoephedrine 30 mg (Table 6).

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Figure 1. Mean Change in Nasal Air Flow after Single Oral Doses of Pseudoephedrine in Subjects with Allergic Rhinitis

Note: Time 0 = time of administration of study medication. Min = minutes.

14.2 Comparative Bioavailability Studies

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

In a 4-way, randomized, cross-over comparative bioavailability study conducted with healthy male and female volunteers (N=27), Advil Cold & Sinus Liqui-Gels [2 x (200 mg ibuprofen/30 mg pseudoephedrine hydrochloride)] were compared to Advil Cold and Sinus Caplets [2 x (200 mg ibuprofen/30 mg pseudoephedrine hydrochloride)], Children’s Sudafed Nasal Decongestant Liquid Medication (2 x 15 mg/5mL pseudoephedrine hydrochloride), and Advil Liqui-Gels (2 x 200 mg ibuprofen). The results from the comparison of Advil Cold and Sinus Liqui-Gels and Advil Cold and Sinus Caplets are presented below in Table 7 (Ibuprofen) and Table 8 (Pseudoephedrine HCl).

* expressed as arithmetic mean (%CV) only.

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

* expressed as arithmetic mean (%CV) only.

In a 2-way randomized, cross-over comparative bioavailability study conducted with healthy male and female volunteers (N=26), Advil Cold and Sinus Liqui-Gels [2 x (200 mg ibuprofen/30 mg pseudoephedrine hydrochloride)] under fasting conditions were compared against Advil Cold & Sinus Liqui-Gels [2 x (200 mg ibuprofen/30 mg pseudoephedrine hydrochloride)] under fed conditions. The presence of food decreased the rate but not the extent of absorption of ibuprofen and had no effect on the rate and extent of absorption of pseudoephedrine hydrochloride.

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

Ibuprofen

Single Dose Toxicity Studies

Single-dose toxicity studies have been conducted in mice, rats, and dogs.

The LD₅₀ values for ibuprofen in mice and rats, expressed as mg/kg of body weight, are as follows:

Acute signs of poisoning were prostration in mice and sedation, prostration, loss of righting reflex, and laboured respiration in rats. Death occurred within 3 days from perforated gastric ulcers in mice and intestinal ulceration in rats, irrespective of the route of administration.

Single ibuprofen doses of 125 mg/kg and above in dogs caused emesis, transient albuminuria, faecal blood loss, and erosions in the gastric antrum and pylorus. No ill effects were seen with doses of 20 or 50 mg/kg.

Multi Dose Studies

The primary toxic effect of ibuprofen in repeated doses in rats is intestinal damage. At a dosage of 180 mg/kg/day for 26 weeks, ibuprofen alters the organ-to-body weight ratio of certain organs, such as the liver, kidneys, gonads, and secondary sex organs, although no histological abnormalities have been observed and the effects are reversible. The liver and kidney enlargement may be a reflection of work hypertrophy associated with the metabolism and excretion of the compound, whereas the significance of the effects on other organs is unknown. When administered in lethal doses (540 mg/kg/day), ibuprofen produces mild kidney lesions in addition to intestinal damage.

Carcinogenicity

In rats given 180 mg/kg/day of ibuprofen orally for 55 weeks and 60 mg/kg/day for the next 60 weeks, the only specific pathological effect observed was intestinal ulceration. There was no evidence of tumour induction, indicating that ibuprofen is not carcinogenic in rats. Ibuprofen is not teratogenic when given in toxic doses (60 mg/kg/day) to rabbits or in ulcerogenic doses (180 mg/kg/day to rats.

Teratology Study in Rabbits

New Zealand white rabbits were given 0, 7.5, 20 and 60 mg/kg daily of ibuprofen from day 1 to day 29 of pregnancy. The mean fetal weight was unaffected; litter size was unaffected at the lower doses. Congenital malformations did occur in both treated and untreated groups with no consistent pattern

Ibuprofen and Pseudoephedrine Hydrochloride Tablets

ADVIL COLD & SINUS LIQUI-GELS / ADVIL COLD & SINUS EXTRA STRENGTH LIQUI-GELS Ibuprofen (free acid and potassium salt) and Pseudoephedrine Hydrochloride Capsules CHILDREN’S ADVIL COLD

except for one litter of 4 young with cyclopia. The results of this experiment indicate that ibuprofen is not teratogenic when given in toxic doses to rabbits.

Teratology Study in Rats

Newly-mated female albino rats were given ibuprofen in doses of 0, 7.5, 20, 60 and 180 mg/kg/day from day 1 to day 20 of pregnancy; ibuprofen exhibited no embryotoxic or teratogenic effects even when administered at ulcerogenic doses.

Penetration of Ibuprofen into the Rabbit and Rat Fetus

Rabbits and rats in late pregnancy were given single oral doses of 60 and 20 mg/kg respectively of C¹⁴ labelled ibuprofen. Rabbits were killed three hours after dosing and rats killed 1.5 hours after dosing when maternal and fetal blood was collected. Similar concentrations of radioactive ibuprofen were detected in both the mother and fetus indicating that the drug and its metabolites readily crossed the placental barrier into the fetal circulation.

Pseudoephedrine Hydrochloride

Mice injected with toxic doses of pseudoephedrine manifest increased motor activity, piloerection, and mydriasis, and they eventually die in respiratory exhaustion. The intravenous LD₅₀ in mice is approximately 90 mg/kg. The approximate oral LD₅₀ values are 726 mg/kg (mice), 2206 mg/kg (rats), 1117 mg/kg (rabbits), 105 mg/kg (beagle dogs), and 307 mg/kg (mongrel dogs). Toxic effects of pseudoephedrine include increased respiratory activity, salivation, and lacrimation; loss of pupillary reflex in reaction to light; tremor, convulsions, and cardiac arrhythmias.

The LD₅₀ values for pseudoephedrine, expressed as mg/kg of body weight, are as follows: