IBUPROFEN AND DIPHENHYDRAMINE HYDROCHLORIDE

Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Studies of Ibuprofen and Diphenhydramine in Combination In a 10-day maximum use safety and efficacy study (AE-97-08), a total of 1016 patients between 12 to >65 years of age took either one capsule of ibuprofen 200 mg/diphenhydramine hydrochloride 25 mg (n= 158), or two capsules of ibuprofen 400 mg/diphenhydramine hydrochloride 50 mg (n=323), or two caplets of acetaminophen 1000 mg/diphenhydramine hydrochloride 50 mg (n=326) or and placebo (N=167) for 10 consecutive evenings.

They were instructed to begin taking the study drug on the first evening they experienced sleeplessness associated with a headache or minor aches or pains. They continued to take study medication for the next 9 consecutive evenings, regardless of whether or not they were experiencing symptoms.

Although the duration of use was beyond the maximum over-the-counter duration of use (10 days versus 5 days) of ibuprofen, the daily dose was below the maximum daily dose for ibuprofen of 1200 mg and for diphenhydramine of 150 mg. The study suggests that there are no clinically relevant safety concerns associated with ibuprofen and diphenhydramine hydrochloride capsules when administered once a day at a dose of ibuprofen / diphenhydramine hydrochloride (400 mg/50 mg or 200 mg/25 mg) [132].

S. marketed analgesic/sleep-aid product consisting of acetaminophen 1000 mg/diphenhydramine hydrochloride 50 mg. The incidences of these symptoms were similar for both doses of ibuprofen / diphenhydramine (400 mg/50 mg vs. 200 mg/25 mg).

The AEs with incidence rates exceeding 2% in any treatment group are presented in Table 1. These finding were consistent within all age and gender subgroups, indicating that the use of the combination of ibuprofen and diphenhydramine by the elderly poses no additional safety concerns [132].

Page 13 of 48 Table 1. S. 05 are bolded. Two placebo-controlled, double-blind clinical trials (AE-98-01 and AE-98-02) studied subjects 16-45 years of age who had undergone surgical removal of 1 or 2 impacted third molars, one of which was at least a partial bony mandibular impaction, were given a single dose of either placebo ibuprofen (400mg) /diphenhydramine (50 mg) or 400 mg ibuprofen (n=118), before bedtime on the day of surgery.

Study AE-98-01 involved 281 subjects, with 40 receiving placebo, 122 receiving ibuprofen (400 mg) /diphenhydramine (50 mg) and 118 receiving 400 mg ibuprofen The active treatments were well tolerated [123]. 9% in the ibuprofen group.

The AEs with incidence rates exceeding 2% in any treatment group are presented in Table 2. 8%). There were no serious AEs. Page 14 of 48 Table 2. 10). Study AE-98-02 involved 283 subjects, with 40 receiving placebo, 120 receiving ibuprofen (400 mg) /diphenhydramine (50 mg) and 123 receiving 400 mg ibuprofen.

7% in the ibuprofen group [124]. The AEs with incidence rates exceeding 2% in any treatment group are presented in Table 3. There was a significant […]

Serious Warnings and Precautions  Causes sedation or sleepiness. Not for daytime use.  Caution in patients prone to gastrointestinal tract irritation (See Warnings and Precautions, Gastrointestinal, and Drug Interactions, Coumarin-type anticoagulants).

 Use with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention (See Warnings and Precautions, Cardiovascular and Fluid and Electrolyte Balance; and Drug Interactions, Antihypertensives).

 Patients at greatest risk of renal toxicity are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and the elderly (See Warnings and Precautions, Renal).  If urinary symptoms, hematuria and cystitis occur, the drug should be stopped immediately (See Warnings and Precautions, Genitourinary).

 Ibuprofen use during pregnancy/nursing should be avoided (See Warnings and Precautions, Special Populations: Pregnant Women and Nursing Women). General As with other anti-inflammatory drugs, ibuprofen may mask the usual signs of infection.

Ibuprofen is NOT recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions. (See Drug Interactions – Drug/Drug Interactions – Acetylsalicylic acid (ASA) or other NSAIDs).

Patients who suffer from sleeplessness without pain and pain that does not cause sleeplessness should not take this product. Patients with glaucoma, chronic lung disease (emphysema or chronic bronchitis), or difficulty in urination due to prostate enlargement or bladder neck problems should not take this product unless directed by a physician [126].

If symptoms of acute pain and sleeplessness caused by pain do not improve within 5 days or are accompanied by fever, patients should stop use and consult a physician. Carcinogenesis and Mutagenesis Not applicable.

Cardiovascular Ibuprofen:

Congestive heart failure in patients with marginal cardiac function, elevated blood pressure and palpitations. Long term continuous use may increase the risk of heart attack or stroke [136].

Diphenhydramine:

Vasconstrictive effects have been noted [17]. Page 6 of 48 Dependence/Tolerance A combination of butorphanol and diphenhydramine is being increasingly used as a drug of abuse. Diphenhydramine dependence has been documented in case reports involving mentally ill patients [17].

Ear/Nose/Throat Patients with complete or partial syndrome of nasal polyps should not use Ibuprofen and Diphenhydramine Hydrochloride Capsules (See Contraindications). Endocrine and Metabolism Patients with thyroid disease should not take this drug unless directed by a physician.

Fluid and Electrolyte Balance Fluid retention and oedema have been observed in patients treated with ibuprofen. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind.

Ibuprofen and Diphenhydramine Hydrochloride Capsules 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 Serious gastrointenstinal (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 NSAIDs, 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. Ibuprofen and Diphenhydramine Hydrochloride Capsules should be given under close medical supervision to patients prone to GI 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. 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 GI ulceration or bleeding.

Because serious GI tract ulceration Page 7 of 48 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, Ibuprofen and Diphenhydramine Hydrochloride Capsules 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.

The major risk factors are a prior history of serious GI events and increasing age. Possible risk factors include other factors such as Helicobacter pylori […]

 Ibuprofen is contraindicated for patients with active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system.  Both ibuprofen and diphenhydramine have been associated with hypersensitivity.

Patients who are hypersensitive to these drugs or to any ingredient in the formulation or component of the container should not use this product. For a complete listing, see Dosage Forms, Composition and Packaging Section of the product monograph.

The potential for cross-reactivity between different NSAIDs must be kept in mind.  Ibuprofen containing products should not be used in patients with the complete or partial syndrome of nasal polyps, or in whom asthma, anaphylaxis, urticaria, rhinitis or other allergic manifestations are precipitated by 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.  Do not use Ibuprofen and Diphenhydramine Hydrochloride Capsules during the last 3 months of pregnancy [17].

 Ibuprofen should not be used right before or after heart surgery.  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 and Diphenhydramine Hydrochloride Capsules 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.  Children 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.

 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.  Ibuprofen should not be used in the presence of known hyperkalemia (also see Warnings and Precautions – Renal section).

 Ibuprofen and Diphenhydramine Hydrochloride Capsules should not be used during the last 3 months of pregnancy [17], or by Nursing Mothers.  Children and adolescents (see Indications). Page 5 of 48 WARNINGS AND PRECAUTIONS Serious Warnings and Precautions  Causes sedation or sleepiness.

Not for daytime use.  Caution in patients prone to gastrointestinal tract irritation (See Warnings and Precautions, Gastrointestinal, and Drug Interactions, Coumarin-type anticoagulants).  Use with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention (See Warnings and Precautions, Cardiovascular and Fluid and Electrolyte Balance; and Drug Interactions, Antihypertensives).

 Patients at greatest risk of renal toxicity are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and the elderly (See Warnings and Precautions, Renal).  If urinary symptoms, hematuria and cystitis occur, the drug should be stopped immediately (See Warnings and Precautions, Genitourinary).

 Ibuprofen use during pregnancy/nursing should be avoided (See Warnings and Precautions, Special Populations: Pregnant Women and Nursing Women). General As with other anti-inflammatory drugs, ibuprofen may mask the usual signs of infection.

Ibuprofen is NOT recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions. (See Drug Interactions – Drug/Drug Interactions – Acetylsalicylic acid (ASA) or other NSAIDs).

Patients who suffer from sleeplessness without pain and pain that does not cause sleeplessness should not take this product. Patients with glaucoma, chronic lung disease (emphysema or chronic bronchitis), or difficulty in urination due to prostate enlargement or bladder neck problems should not take this product unless directed by a physician [126].

If symptoms of acute pain and sleeplessness caused by pain do not improve within 5 days or are accompanied by fever, patients should stop use and consult a physician. Carcinogenesis and Mutagenesis Not applicable.

Cardiovascular Ibuprofen:

Congestive heart failure in patients with marginal cardiac function, elevated blood pressure and palpitations. Long term continuous use may increase the risk of heart attack or stroke [136].

Diphenhydramine:

Vasconstrictive effects have been noted [17]. Page 6 of 48 Dependence/Tolerance A combination of butorphanol and diphenhydramine is being increasingly used as a drug of abuse. Diphenhydramine dependence has been documented in case reports involving mentally ill patients [17].

Ear/Nose/Throat Patients with complete or partial syndrome of nasal polyps should not use Ibuprofen and Diphenhydramine Hydrochloride Capsules (See Contraindications). Endocrine and Metabolism Patients with thyroid disease should not take this drug unless directed by a physician.

Fluid and Electrolyte Balance Fluid retention and oedema have been observed in patients treated with ibuprofen. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind.

Ibuprofen and Diphenhydramine Hydrochloride Capsules 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 […]