Diphenhydramine

Diphenhydramine is an H1-Receptor Antihistamine.

It is used to prevent and treat Anaphylaxis, Insomnia, it is also used to treat Angioedema, allergic (acute); Infusion- or transfusion-related reactions; Nausea and vomiting, pregnancy associated, severe or refractory; Scombroid (histamine) poisoning; Urticaria, new onset and chronic spontaneous; Vertigo, acute episodes

Diphenhydramine is Well absorbed from the gastrointestinal tract. Bioavailability: 42-62%. It is Widely distributed throughout the body including the CNS. Crosses the placenta, enters breastmilk. Volume of distribution: 17 L/kg. Plasma protein binding: 98.5%.

It is Extensively metabolised in the liver by CYP2D6 isoenzyme via N-demethylation and minor demethylation by CYP1A2, 2C9, 2C19; smaller degrees in pulmonary and renal systems; undergoes significant first-pass effect.

and get excreted Mainly via urine (as metabolites and unchanged drug). Elimination half-life: 2.4-9.3 hours.

The Duration of Action of Diphenhydramine is Histamine-induced wheal suppression: ≤10 hours; histamine-induced flare suppression: ≤12 hours.

Diphenhydramine shows common side effects like Insomnia, nervousness, irritability, anxiety.Respiratory, thoracic and mediastinal disorders: Elevated respiration.

Diphenhydramine is available in the form of oral liquid, elixir, Syrup, Tablets, Capsules and injectable solutions .

Diphenhydramine is available in India, Germany, Canada, Italy.

Diphenhydramine, a monoethanolamine derivative, is an antihistamine with sedative and anti-cholinergic activity. It competes with histamine for H1 receptor sites on effector cells in the blood vessels, gastrointestinal tract, and respiratory tract.

Diphenhydramine is available in the form of oral liquid, elixir, Syrup, Tablets, Capsules and injectable solutions.

Oral: When used to prevent motion sickness, first dose should be given 30 minutes prior to exposure. When used for occasional insomnia, dose should be given 30 minutes before bedtime.

IM, IV: Injection solution is for IV or deep IM administration only. For IV administration, inject at a rate ≤25 mg/minute. Local necrosis may result with Subcutaneous or intradermal use.

It is used to prevent and treat Anaphylaxis, Insomnia, it is also used to treat Angioedema, allergic (acute); Infusion- or transfusion-related reactions; Nausea and vomiting, pregnancy associated, severe or refractory; Scombroid (histamine) poisoning; Urticaria, new onset and chronic spontaneous; Vertigo, acute episodes

Diphenhydramine is approved for use in the following clinical indications

Symptomatic relief of allergic symptoms caused by histamine release, including nasal allergies and allergic dermatosis; adjunct to epinephrine in the treatment of anaphylaxis; insomnia (occasional); prevention or treatment of motion sickness; antitussive; management of drug-induced extrapyramidal symptoms (eg, dystonia, parkinsonism) and parkinsonian syndrome alone or in combination with centrally acting anticholinergic agents.

Anaphylaxis: Antihistamines are considered second-line treatment only after epinephrine administration in the adjunct management of anaphylaxis.

Insomnia: American Academy of Sleep Medicine guidelines for the treatment of chronic insomnia suggest diphenhydramine not be used for sleep-onset or sleep-maintenance insomnia in adults due to the absence of evidence for clinically significant improvement . The US Department of Veterans Affairs/Department of Defense guidelines for the chronic management of insomnia disorder and obstructive sleep apnea suggest against the use of diphenhydramine for chronic insomnia.

• Although not approved there have been certain off label use documented for Diphenhydramine which includes

Angioedema, allergic (acute); Infusion- or transfusion-related reactions; Nausea and vomiting, pregnancy associated, severe or refractory; Scombroid (histamine) poisoning; Urticaria, new onset and chronic spontaneous; Vertigo, acute episodes

Oral

• Allergic conditions

Adult: 25-50 mg 3 or 4 times daily. Max: 300 mg daily. For prevention of motion sickness, administer 30 minutes before exposure to motion.

Child: 2-6 years 6.25 mg 4-6 hourly; 6-12 years 12.5-25 mg 4-6 hourly; >12 years Same as adult dose. For prevention of motion sickness, administer 30 minutes before exposure to motion.

• Motion sickness

Adult: 25-50 mg 3 or 4 times daily. Max: 300 mg daily. For prevention of motion sickness, administer 30 minutes before exposure to motion.

Child: 2-6 years 6.25 mg 4-6 hourly; 6-12 years 12.5-25 mg 4-6 hourly; >12 years Same as adult dose. For prevention of motion sickness, administer 30 minutes before exposure to motion.

• Short-term management of insomnia

Adult: 50 mg given 30 minutes before bedtime as needed.

Parenteral

• Motion sickness

Adult: 10-50 mg up to 100 mg if needed via IV inj at a rate of 25 mg/min or deep IM inj. Max: 400 mg daily. For prevention of motion sickness, administer 30 minutes before exposure to motion.

Child: 5 mg/kg via IV inj at a rate of 25 mg/min or deep IM inj in 4 divided doses. Max: 300 mg daily. For prevention of motion sickness, administer 30 minutes before exposure to motion.

Incompatibility: IV/IM: Incompatible with amphotericin B, cefmetazole, cefalotin, hydrocortisone Na succinate, soluble barbiturates, contrast media, and strong acids or alkali solutions.

• Allergic conditions

Adult: 10-50 mg up to 100 mg if needed via IV inj at a rate of 25 mg/min or deep IM inj. Max: 400 mg daily. For prevention of motion sickness, administer 30 minutes before exposure to motion.

Child: 5 mg/kg via IV inj at a rate of 25 mg/min or deep IM inj in 4 divided doses. Max: 300 mg daily. For prevention of motion sickness, administer 30 minutes before exposure to motion.

Incompatibility: IV/IM: Incompatible with amphotericin B, cefmetazole, cefalotin, hydrocortisone Na succinate, soluble barbiturates, contrast media, and strong acids or alkali solutions.

• Parkinson’s disease

Adult: 10-50 mg up to 100 mg if needed, via IV inj at a rate not exceeding 25 mg/min or via deep IM inj, when oral therapy is impossible or contraindicated. Max: 400 mg daily.

Incompatibility: IV/IM: Incompatible with amphotericin B, cefmetazole, cefalotin, hydrocortisone Na succinate, soluble barbiturates, contrast media, and strong acids or alkali solutions.

Topical/Cutaneous

• Pruritic skin disorders

Adult: As 2% cream: Apply to affected area(s) up to max bid for not more than 3 days.

Child: ≥2 years Same as adult dose.

Diphenhydramine is available in various strengths as 12.5mg/5mL, 50mg/30mL, 25 mg, 50 mg, 12.5 mg

Diphenhydramine is available in the form of oral liquid, elixir, Syrup, Tablets, Capsules and injectable solutions.

Dosage Adjustment in Kidney Patient

● Altered kidney function: IM, IV, Oral: No dosage adjustment necessary for any degree of kidney function (little excreted unchanged in urine) (Ref).

● Hemodialysis: IM, IV, Oral: Unlikely to be significantly dialyzed (large Vd); no dosage adjustment or supplemental dose necessary.

● Peritoneal dialysis: IM, IV, Oral: Unlikely to be significantly dialyzed (large Vd); no dosage adjustment necessary

● CRRT: IM, IV, Oral: Unlikely to be significantly dialyzed (large Vd); no dosage adjustment necessary.

● PIRRT: IM, IV, Oral: Unlikely to be significantly dialyzed (large Vd); no dosage adjustment necessary

Dosage Adjustment in Hepatic impairment Patient

• There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, use caution in severe impairment due to the potential for altered pharmacokinetics.

Dosage Adjustment for Pediatric Patients:-

• Allergic rhinitis/rhinoconjunctivitis (including upper respiratory allergies or hay fever):

Note: Due to adverse effects (paradoxical agitation/excitation or sedation), H₁ antihistamines (eg, diphenhydramine) are not recommended as first-line therapy for management of allergic rhinitis in pediatric patients; second-generation minimally sedating antihistamines are preferred (Ref).

Infants and Children: Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours as needed; usual dose: 12.5 to 25 mg/dose; maximum dose: 50 mg/dose.

Adolescents: Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours as needed; usual dose: 25 to 50 mg/dose; maximum dose: 50 mg/dose.

● Anaphylaxis, adjunct to epinephrine:

Note: Administer epinephrine first when treating anaphylaxis. Do not use diphenhydramine as initial therapy; H1 antihistamines will not alleviate stridor, shortness of breath, wheezing, GI symptoms, hypotension, or shock and are considered second- or third-line agents in the management of anaphylaxis.

Infants and Children: IV, IM, Oral: 1 mg/kg/dose; maximum dose: 50 mg/dose; may repeat every 6 to 8 hours.

Adolescents: IV, IM, Oral: 25 to 50 mg/dose; may repeat every 4 to 8 hours.

Cutaneous disorders with pruritus (eg, urticaria, atopic dermatitis, other pruritic skin conditions):

Note: First-generation antihistamines (eg, diphenhydramine) are not recommended as first-line agents for urticaria (acute or chronic) due to risk of adverse reactions; second-generation antihistamines are preferred (Ref). For atopic dermatitis, diphenhydramine may provide intermittent relief of pruritus and may help with sleep loss associated with the pruritus; however, it does not treat underlying condition and is not a substitute for topical therapy. Chronic use is not recommended . Dosing recommendations are based on general dosing range in the manufacturer’s labeling

Infants and Children: Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours as needed; usual dose: 12.5 to 25 mg/dose; maximum dose: 50 mg/dose.

Adolescents: Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours as needed; usual dose: 25 to 50 mg/dose; maximum dose: 50 mg/dose.

Extrapyramidal symptoms (EPS) (eg, medication-induced dystonic reactions):

Acute treatment:

Infants, Children, and Adolescents:

Initial: IV (preferred), IM, Oral: 1 to 2 mg/kg/dose; maximum dose: 50 mg/dose; may repeat in 30 minutes if no response. Oral therapy may be considered for home use while medical care is sought.

Subsequent doses (if needed): IV, Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours for up to 2 to 5 days may be considered to prevent recurrence. Maximum dose: 50 mg/dose.

Pretreatment: Limited data available: Note: Recommended for use when high-dose metoclopramide is required and should be considered when use of other medications known to have a high risk of EPS (eg, high-dose chlorpromazine or prochlorperazine) are required. Diphenhydramine has not been shown to prevent akathisia symptoms.

Children and Adolescents: IV: 0.5 to 1 mg/kg/dose concomitantly with high-risk medication; repeat dose may be necessary with continued therapy depending on administered medication. Maximum dose: 50 mg/dose. Higher doses of 2 mg/kg/dose (maximum dose: 50 mg/dose) have also been reported in children ≥5 years and adolescents.

Infusion or transfusion reactions:

Premedication (eg, radiocontrast agents, IVIG, monoclonal antibody therapy, chemotherapy): Limited data available: Note: Use of premedication should be individualized to patient factors and institutional protocols; may be given in combination with acetaminophen, corticosteroids, and/or H2 antihistamines. For blood products, pretreatment is not routinely recommended because use has not been shown to significantly impact the rate of allergic reaction.

Infants, Children, and Adolescents: IV, Oral: 1 mg/kg/dose administered 30 to 60 minutes prior to infusion; maximum dose: 50 mg/dose

Treatment: Limited data available: Note: If patient is experiencing anaphylaxis, administer epinephrine first. Do not use diphenhydramine for initial or sole treatment of anaphylaxis because H1 antihistamines do not relieve upper or lower airway obstruction, hypotension, or shock. Diphenhydramine should be used for symptomatic relief as an adjunct to other appropriate measures (eg, stopping the infusion, reducing the infusion rate)

Infants and Children: IV: 1 mg/kg/dose; maximum dose: 50 mg/dose; may repeat every 6 to 8 hours.

Adolescents: IV, IM, Oral: 25 to 50 mg/dose; may repeat every 4 to 8 hours .

Insomnia, occasional:

Note: Efficacy results are variable. Evaluation of sleep hygiene and use of nonpharmacologic (ie, behavioral) treatment are preferred; medications may be used as adjunct treatment. While diphenhydramine has been shown to improve sleep latency and reduce nighttime awakenings in children 2 to 12 years of age, studies have not supported the use of diphenhydramine to improve sleep in younger children or infants; routine use is not recommended in adults

Children ≥2 years and Adolescents: Limited data are available for children <12 years: Oral: 0.5 to 1 mg/kg administered 30 minutes before bedtime as needed; usual dose: 12.5 to 50 mg/dose; maximum dose: 50 mg/dose.

Nausea and vomiting:

General dosing: Limited data available: Note: Diphenhydramine may be used for both its antihistamine (causing drowsiness) and antimuscarinic (reducing nausea) effects as adjunct therapy with antiemetics to manage nausea and vomiting associated with various presenting conditions (eg, chemotherapy-induced nausea/vomiting, cyclic vomiting syndrome, migraine, palliative care) .

Infants, Children, and Adolescents: IV, IM, Oral: 0.625 to 1.25 mg/kg/dose every 6 hours; maximum dose: 50 mg/dose .

Motion sickness:

Prophylaxis: Note: First dose should be administered 30 to 60 minutes before travel.

Children: Oral: 0.5 to 1 mg/kg/dose every 6 hours during triggering motion; usual dose: 12.5 to 25 mg/dose; maximum dose: 25 mg/dose.

Adolescents: Oral: 12.5 to 25 mg every 6 to 8 hours during triggering motion.

Treatment:

Infants, Children, and Adolescents:

IV, IM: 1.25 mg/kg/dose every 6 hours as needed; maximum dose: 50 mg/dose. Note: Usual adult dose: 10 to 50 mg/dose.

Oral: 5 mg/kg/day in equally divided doses administered every 6 to 8 hours as needed; usual dose: 12.5 to 25 mg/dose; maximum dose: 50 mg/dose.

Scombroid (histamine) poisoning:

Note: May be useful for patients with uncomfortable symptoms (eg, flushing, burning, rash) but without respiratory distress or hypotension. For patients with moderate to severe symptoms, utilize the IV route.

Very limited data available: Children and Adolescents: IV, Oral: 1 mg/kg/dose; maximum dose: 50 mg/dose. May repeat every 6 to 8 hours if necessary; however, most symptoms should resolve within 6 to 8 hours after the initial dose

Hypersensitivity to diphenhydramine, other structurally related antihistamines, or any component of the formulation; neonates or premature infants; breast-feeding

Additional contraindications: Parenteral: Use as a local anesthetic

OTC labeling: When used for self-medication, do not use in children <6 years, to make a child sleep, or with any other diphenhydramine-containing products (including topical products)

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Disease-related concerns:

• Asthma: Use with caution in patients with a history of asthma.

• Cardiovascular disease: Use with caution in patients with cardiovascular disease (including hypertension and ischemic heart disease).

• Increased intraocular pressure/glaucoma: Use with caution in patients with increased intraocular pressure or angle-closure glaucoma.

• Prostatic hyperplasia/urinary obstruction: Use with caution in patients with prostatic hyperplasia, bladder neck obstruction, and/or GU obstruction.

• Pyloroduodenal obstruction: Use with caution in patients with pyloroduodenal obstruction (including stenotic peptic ulcer).

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Diphenhydramine is only indicated for use in premature neonates.

Diphenhydramine is only indicated for use in premature neonates.

High-fat meal may decrease the rate but not the extent of absorption. Management: May administer with meals.

• Common Adverse effects:

Dry mouth, epigastric distress, nausea, vomiting, diarrhea, constipation.

• Less Adverse effects:

Anorexia. Nervous system disorders: Sedation, drowsiness, restlessness, dizziness, excitability (children), headache.

• Rare Adverse effects:

Thickening of bronchial secretions. Skin and subcutaneous tissue disorders: Sensitization reaction, photosensitivity. Vascular disorders: Hypotension.

May increase sedative effects of other CNS depressants (e.g. tranquilizers, hypnotics, anxiolytics). Enhanced and prolonged anticholinergic effects with MAOIs. May potentiate effects of anticholinergic agents (e.g. atropine, TCA). May diminish therapeutic effect of betahistine.

The common side effects of Diphenhydramine include the following Psychiatric disorders: Insomnia, nervousness, irritability, anxiety.

Respiratory, thoracic and mediastinal disorders: Elevated respiration.

Potentially Fatal: Necrotising enterocolitis.

Symptoms: Drowsiness, sedation, mydriasis, fever, flushing, agitation, tremor, dystonic reactions, hallucination, ECG changes. Severe cases: Rhabdomyolysis, convulsions, delirium, toxic psychosis, arrhythmias, coma, cardiovascular collapse. May result in hallucinations, convulsions and death in paediatrics patients.

Management: Supportive and symptomatic treatment. Administer parenteral diazepam for treatment of convulsions and marked CNS stimulation. May give vasopressors to treat hypotension.

Pharmacodynamic

Diphenhydramine has anti-histaminic (H1-receptor), anti-emetic, anti-vertigo and sedative and hypnotic properties . The anti-histamine action occurs by blocking the spasmogenic and congestive effects of histamine by competing with histamine for H1 receptor sites on effector cells, preventing but not reversing responses mediated by histamine alone . Such receptor sites may be found in the gut, uterus, large blood vessels, bronchial muscles, and elsewhere

Pharmacokinetics

• Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: 42-62%. Time to peak plasma concentration: Approx: 1-4 hours.
• Distribution: Widely distributed throughout the body including the CNS. Crosses the placenta, enters breastmilk. Volume of distribution: 17 L/kg. Plasma protein binding: 98.5%.
• Metabolism: Extensively metabolised in the liver by CYP2D6 isoenzyme via N-demethylation and minor demethylation by CYP1A2, 2C9, 2C19; smaller degrees in pulmonary and renal systems; undergoes significant first-pass effect.
• Excretion: Mainly via urine (as metabolites and unchanged drug). Elimination half-life: 2.4-9.3 hours.

• https://www.rxlist.com/dopram-drug.htm
• https://www.mims.com/india/drug/info/Diphenhydramine ?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00561
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003846/