Applies to diphenhydramine / ibuprofen: oral tablet.

Serious side effects

Along with its needed effects, diphenhydramine/ibuprofen may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking diphenhydramine / ibuprofen:

Incidence not known

• Bloody or black, tarry stools
• chest pain, discomfort, or tightness
• confusion
• constipation
• decreased urine output
• diarrhea
• difficulty in speaking
• dilated neck veins
• double vision
• headache
• heartburn
• inability to move the arms, legs, or facial muscles
• inability to speak
• indigestion
• irregular breathing
• irregular heartbeat
• nausea
• pain or discomfort in the arms, jaw, back, or neck
• severe stomach pain
• slow speech
• stomach cramping or burning
• sweating
• swelling of the face, fingers, feet, or lower legs
• trouble breathing
• vomiting
• vomiting of blood or material that looks like coffee grounds
• weight gain

For Healthcare Professionals

Applies to diphenhydramine / ibuprofen: oral capsule, oral tablet.

General

The more commonly reported adverse effects include drowsiness and dyspepsia.^[Ref]

Cardiovascular

Diphenhydramine:

Frequency not reported: Hypotension, tachycardia, palpitations

Ibuprofen:

Common (1% to 10%): Peripheral edema

Uncommon (Less than 1%): Elevated blood pressure^[Ref]

Nervous system

The CNS depressant effect of diphenhydramine parallels its plasma concentrations. The plasma concentration threshold for sedation is 30 to 42 ng/mL, and to cause mental impairment is 58 to 74 ng/mL. Dystonic reactions have been accompanied by dizziness, mental confusion, rigidity, lip and tongue protrusion, trismus, torticollis, and swallowing difficulties and generally resolve spontaneously. Delirium has been reported in elderly patients with mild dementia following a small oral dose of diphenhydramine.

The incidence of aseptic meningitis associated with ibuprofen is higher in patients with systemic lupus erythematosus and other connective tissue disease, although it has been reported in patients without such underlying disease states.^[Ref]

Diphenhydramine:

Very common (Greater than 10%): Drowsiness, sedation

Frequency not reported: Impaired motor skills, dystonic reactions, delirium

Ibuprofen:

Rare (less than 0.1%): Aseptic meningitis, paresthesias, and pseudotumor cerebri

Frequency not reported: Headache, drowsiness, dizziness^[Ref]

Gastrointestinal

Diphenhydramine:

Frequency not reported: Nausea, dry mouth

Ibuprofen:

Frequency not reported: Dyspepsia, nausea, diarrhea, abdominal pain, flatulence^[Ref]

More serious gastrointestinal effects of ibuprofen are uncommon but include occult blood loss, ulcer, gastrointestinal hemorrhage with or without perforation, and pancreatitis. In addition, a case of ibuprofen-associated colitis has been reported.

The incidence of gastrointestinal blood loss with ibuprofen is dose-related, occurring in up to 17% of patients receiving 1,600 mg per day and in 23% of patients receiving 2,400 mg per day.

Patients with a history of serious gastrointestinal events or alcohol abuse are at increased risk for severe gastrointestinal side effect. Ibuprofen should be used with caution in these patients.^[Ref]

Renal

Ibuprofen:

Frequency not reported: New or worsened renal insufficiency, nephrotic syndrome with and without renal failure, acute renal failure due to tubulointerstitial nephritis, papillary necrosis, and acute tubular necrosis^[Ref]

Ibuprofen may impair the ability of the kidney to cope with low renal blood flow states due to inhibition of prostaglandin-dependent afferent arteriolar vasodilation. Renal function may be further compromised in patients with heart failure, hypovolemia, cirrhosis, nephrotic syndrome, or hypoalbuminemia. Additional risk factors for ibuprofen-induced renal insufficiency are advanced age and concomitant use of diuretics.

A case-controlled study suggested that patients who consumed 5000 or more pills containing NSAIDs during their lifetime may be at increased risk of end-stage renal disease.^[Ref]

Hypersensitivity

Diphenhydramine:

Frequency not reported: Rash, pruritus, eczema, photosensitivity reactions

Ibuprofen:

Frequency not reported: Erythematous or urticarial rashes, pruritus, angioedema, bronchospasm, anaphylactoid reactions^[Ref]

Most commonly, hypersensitivity to diphenhydramine has manifested itself in patients receiving systemic drug after being sensitized to it by topical application. Sensitization with systemic administration has also been reported.

Patients who are at higher risk of hypersensitivity reactions to ibuprofen include those with the syndrome of asthma, nasal polyps, and angioedema and/or bronchospastic reactivity to aspirin. Rare cases of systemic reactions, including interstitial nephritis and diffuse pulmonary infiltrates, have also been reported.^[Ref]

Genitourinary

Diphenhydramine:

Frequency not reported: Urinary retention, dysuria^[Ref]

Hematologic

Diphenhydramine:

Frequency not reported: Hemolytic anemia, thrombocytopenia, agranulocytosis

Ibuprofen:

Frequency not reported: Platelet dysfunction, neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia, thrombocytopenia, eosinophilia, decreases in hemoglobin and hematocrit^[Ref]

Reductions in serum hemoglobin concentrations are uncommon and are usually associated with occult gastrointestinal blood loss. Rare cases of ibuprofen-associated hemolytic anemia, autoimmune thrombocytopenia, and leukopenia have been reported.^[Ref]

Ocular

Diphenhydramine:

Frequency not reported: Blurred vision, diplopia, dry eyes

Ibuprofen:

Rare (less than 1%): Blurred vision

Frequency not reported: Scotomata, diplopia^[Ref]

Dermatologic

Ibuprofen:

Frequency not reported: Maculopapular rash, pruritus, vesiculobullous eruptions, erythema multiforme, Stevens-Johnson syndrome, alopecia, toxic epidermal necrolysis, photosensitivity reactions^[Ref]

Hepatic

Ibuprofen:

Very common (over 10%): Elevations in liver function tests (15%)

Frequency not reported: Jaundice, hepatitis^[Ref]

Elevations in liver function tests three times normal values occur in less than 1% of patients treated with ibuprofen. Ibuprofen-induced hepatitis has been associated with a fatal outcome in some cases.^[Ref]

Metabolic

Ibuprofen:

Frequency not reported: Hyponatremia and the Syndrome of Inappropriate Antidiuretic Hormone (SIADH), gynecomastia, hypoglycemia, metabolic acidosis^[Ref]

Respiratory

Acute noncardiogenic pulmonary edema developed on two occasions in an HIV-positive patient. Infectious as well as cardiac etiologies were excluded. A close temporal relationship with the administration of ibuprofen and onset of symptoms was noted.^[Ref]

Ibuprofen:

Frequency not reported: Noncardiogenic pulmonary edema^[Ref]

Psychiatric

Ibuprofen:

Frequency not reported: Depression^[Ref]

Other

Ibuprofen:

Common (1% to 10%): Tinnitus

Frequency not reported: Vertigo