Benadryl Allergy Liquid Release 10mg Capsules

Capsule, soft. Each capsule has a colourless to slightly yellow, clear shell containing a clear, colourless viscous fill. Each soft gel capsule has the logo "C10" printed with black ink.

4.1 Therapeutic indications Benadryl Allergy Liquid Release 10 mg Capsules is indicated in children aged 12 years and above, adolescents and adults: o for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis. o for the relief of symptoms of chronic idiopathic urticaria.4.2 Posology and method of administration **Adults and adolescents 12 years of age and over:** 10 mg once daily (1 capsule). The capsules need to be swallowed with a glass of liquid. **Elderly subjects**: data do not suggest that the dose needs to be reduced in elderly subjects provided that the renal function is normal. **Patients with moderate to severe renal impairment:** the dosing intervals must be individualized according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr (ml/min) may be estimated from serum creatinine (mg/dl) determination using the following formula: Dosing adjustments for adult patients with impaired renal function | | | | | --- | --- | --- | | Group | Creatinine clearance (ml/min) | Dosage and frequency | | Normal | ≥80 | 10 mg once daily | | Mild | 50 – 79 | 10 mg once daily | | Moderate | 30 – 49 | 5 mg once daily\* | | Severe | < 30 | 5 mg once every 2 days\* | | End-stage renal disease - Patients undergoing dialysis | < 10 | Contra-indicated | \* The product cannot be halved to give the required dose adjustment in renally-impaired patients. In paediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient, and his body weight. **Patients with hepatic impairment**: no dose adjustment is needed in patients with solely hepatic impairment. **Patients with hepatic impairment and renal impairment**: adjustment of the dose is recommended (see Patients with renal impairment above).4.3 Contraindications Hypersensitivity to cetirizine dihydrochloride, to hydroxyzine, to any piperazine derivatives, to soya, peanut, or to any of the excipients listed in section 6.1. Patients with moderate to severe renal impairment at less than 50 ml/min creatinine clearance (as the product cannot be halved to give the required dose adjustment).4.4 Special warnings and precautions for use At therapeutic doses, no clinically significant interactions have been demonstrated with alcohol (for a blood alcohol level of 0.5 g/L). Nevertheless, precaution is recommended if alcohol is taken concomitantly. Patients with both liver and kidney disease should consult a physician before use. The physician should determine if a different dose is needed. Caution should be taken in patients with predisposition factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as cetirizine may increase the risk of urinary retention. Caution in epileptic patients and patients at risk of convulsions is recommended. Allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them. This product contains a maximum of 19.3mg sorbitol (E420) per capsule. Pruritus and/or urticaria may occur when cetirizine is stopped, even if those symptoms were not present before treatment initiation. In some cases, the symptoms may be intense and may require treatment to be restarted. The symptoms should resolve when the treatment is restarted. If symptoms persist or worsen, stop use and consult a physician. Paediatric Population The use of the capsule formulation is not recommended in children aged less than 12 years since this formulation does not allow for appropriate dose adaptation.4.5 Interaction with other medicinal products and other forms of interaction Due to the pharmacokinetic, pharmacodynamic and tolerance profile of cetirizine, no interactions are expected with this antihistamine. Actually, neither pharmacodynamic nor significant pharmacokinetic interaction was reported in drug-drug interactions studies performed, notably with pseudoephedrine or theophylline (400 mg/day). The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased.4.6 Fertility, pregnancy and lactation This product should not be used during pregnancy or breastfeeding unless the potential benefit of treatment to the mother outweighs the possible risks to the developing foetus or breastfeeding infant. **Pregnancy** For cetirizine very rare clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women. **Lactation** Cetirizine is excreted in human milk at concentrations representing 25% to 90% those measured in plasma, depending on sampling time after administration. Therefore, caution should be exercised when prescribing cetirizine to lactating women. **Fertility** Limited data is available on human fertility but no safety concern has been identified. Animal data show no safety concern for human reproduction4.7 Effects on ability to drive and use machines Objective measurements of driving ability, sleep latency and assembly line performance have not demonstrated any clinically relevant effects at the recommended dose of 10 mg. Patients intending to drive, engaging in potentially hazardous activities or operating machinery should not exceed the recommended dose and should take their response to the medicinal product into account. In sensitive patients, concurrent use with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance, although cetirizine does not potentiate the effect of alcohol (0.5 g/L blood levels). Caution should be used when driving a motor vehicle or operating machinery.4.8 Undesirable effects Clinical studies have shown that cetirizine at the recommended dosage has minor adverse effects on the CNS, including somnolence, fatigue, dizziness and headache. In some cases, paradoxical CNS stimulation has been reported. Although cetirizine is a selective antagonist of peripheral H1-receptors and is relatively free of anticholinergic activity, isolated cases of micturition difficulty, eye accommodation disorders and dry mouth have been reported. Instances of abnormal hepatic function with elevated hepatic enzymes accompanied by elevated bilirubin have been reported. Mostly this resolves upon discontinuation of the drug. **Clinical trials** Double blind controlled clinical trials comparing cetirizine to placebo or other antihistamines at the recommended dosage (10 mg daily for cetirizine), of which quantified safety data are available, included more than 3200 subjects exposed to cetirizine. From this pooling, the following adverse events were reported for cetirizine 10 mg in the placebo-controlled trials at rates of 1.0 % or greater: | | | | | --- | --- | --- | | Adverse event (WHO-ART) | Cetirizine 10 mg (n= 3260) | Placebo (n = 3061) | | Body as a whole – general disorders Fatigue | 1.63 % | 0.95 % | | Central and peripheral nervous system disorders Dizziness Headache | 1.10 % 7.42 % | 0.98 % 8.07 % | | Gastro-intestinal system disorders Abdominal pain Dry mouth Nausea | 0.98 % 2.09 % 1.07 % | 1.08 % 0.82 % 1.14 % | | Psychiatric disorders Somnolence | 9.63 % | 5.00 % | | Respiratory system disorders Pharyngitis | 1.29 % | 1.34 % | Although statistically more common than under placebo, somnolence was mild to moderate in the majority of cases. Objective tests as demonstrated by other studies have demonstrated that usual daily activities are unaffected at the recommended daily dose in healthy young volunteers. Adverse drug reactions at rates of 1 % or greater in children aged from 6 months to 12 years, included in placebo-controlled clinical trials are: | | | | | --- | --- | --- | | Adverse drug reactions (WHO-ART) | Cetirizine (n=1656) | Placebo (n =1294) | | Gastro-intestinal system disorders Diarrhoea | 1.0 % | 0.6 % | | Psychiatric disorders Somnolence | 1.8 % | 1. 4 % | | Respiratory system disorders Rhinitis | 1.4 % | 1.1 % | | Body as a whole – general disorders Fatigue | 1.0 % | 0.3 % | **Post-marketing experience** In addition to the adverse reactions reported during clinical studies and listed above, the following undesirable effects have been reported in post-marketing experience. Undesirable effects are described according to MedDRA System Organ Class and by estimated frequency based on the post-marketing experience. Frequencies are defined as follows: Very common (≥1/10); 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 the available data) *Blood and lymphatic disorders:* Very rare: thrombocytopenia *Immune system disorders:* Rare: hypersensitivity Very rare: anaphylactic shock *Metabolism and nutrition disorders:* Not known: increased appetite *Psychiatric disorders:* Uncommon: agitation Rare: aggression, confusion, depression, hallucination, insomnia Very rare: tics Not known: suicidal ideation, nightmares *Nervous system disorders:* Uncommon: paraesthesia Rare: convulsions Very rare: dysgeusia, dystonia, dyskinesia, syncope, tremor Not known: amnesia, memory impairment *Eye disorders:* Very rare: accommodation disorder, blurred vision, oculogyration, eye swelling Not known: Eye pain *Ear and labyrinth disorders* Not known: vertigo *Cardiac disorders:* Rare: tachycardia *Respiratory, thoracic and mediastinal disorders:* Very rare: Cough *Gastro-intestinal disorders:* Uncommon: diarrhoea *Hepatobiliary disorders:* Rare: hepatic function abnormal (increased transaminases, alkaline phosphatase, γ-GT and bilirubin) Not known: hepatitisa a: Including Drug-induced liver injury (DILI) and other types of non-infectious hepatitis. *Skin and subcutaneous tissue disorders:* Uncommon: pruritus, rash Rare: urticaria Very rare: angioneurotic oedema, fixed drug eruption Not known: acute generalised exanthematous pustulosis (AGEP) *Musculoskeletal and connective tissue disorders:* Not known: arthralgia *Renal and urinary disorders:* Very rare: dysuria, enuresis Not known: urinary retention *Reproductive system and breast disorders:* Not known: erectile dysfunction *General disorders and administration site conditions:* Uncommon: asthenia, malaise Rare: oedema Not known: pruritus upon withdrawal *Investigations:* Rare: weight increased **Reporting of suspected adverse reactions** Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose **Symptoms** Symptoms observed after an overdose of cetirizine are mainly associated with CNS effects or with effects that could suggest an anticholinergic effect. Adverse events reported after an intake of at least 5 times the recommended daily dose are: confusion, diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinary retention. **Management** There is no known specific antidote to cetirizine. Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered following ingestion of a short occurrence. Cetirizine is not effectively removed by dialysis.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Piperazine derivatives, ATC code: R06A E07 Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral H1-receptors. *In vitro* receptor binding studies have shown no measurable affinity for other than H1-receptors. In addition to its anti-H1 effect, cetirizine was shown to display anti-allergic activities: at a dose of 10 mg once or twice daily, it inhibits the late phase recruitment of eosinophils, in the skin and conjunctiva of atopic subjects submitted to allergen challenge. Studies in healthy volunteers show that cetirizine, at doses of 5 and 10 mg strongly inhibits the wheal and flare reactions induced by very high concentrations of histamine into the skin, but the correlation with efficacy is not established. In a 35-day study in children aged 5 to 12, no tolerance to the antihistaminic effect (suppression of wheal and flare) of cetirizine was found. When a treatment with cetirizine is stopped after repeated administration, the skin recovers its normal reactivity to histamine within 3 days. In a six-week, placebo-controlled study of 186 patients with allergic rhinitis and concomitant mild to moderate asthma, cetirizine 10 mg once daily improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering cetirizine to allergic patients with mild to moderate asthma. In a placebo-controlled study, cetirizine given at the high daily dose of 60 mg for seven days did not cause statistically significant prolongation of QT interval. At the recommended dosage, cetirizine has demonstrated that it improves the quality of life of patients with perennial and seasonal allergic rhinitis.5.2 Pharmacokinetic properties The steady - state peak plasma concentrations is approximately 300 ng/ml and is achieved within 1.0 ± 0.5 h. No accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. The distribution of pharmacokinetic parameters such as peak plasma concentration (Cmax) and area under curve (AUC), is unimodal in human volunteers. The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased. The extent of bioavailability is similar when cetirizine is given as solutions, capsules or tablets. The apparent volume of distribution is 0.50 l/kg. Plasma protein binding of cetirizine is 93 ± 0.3 %. Cetirizine does not modify the protein binding of warfarin. Cetirizine does not undergo extensive first pass metabolism. About two third of the dose are excreted unchanged in urine. The terminal half-life is approximately 10 hours. Cetirizine exhibits linear kinetics over the range of 5 to 60 mg. **Special populations** *Elderly*: Following a single 10 mg oral dose, half-life increased by about 50 % and clearance decreased by 40 % in 16 elderly subjects compared to the normal subjects. The decrease in cetirizine clearance in these elderly volunteers appeared to be related to their decreased renal function. *Children, infants and toddlers*: The half-life of cetirizine was about 6 hours in children of 6-12 years and 5 hours in children 2-6 years. In infants and toddlers aged 6 to 24 months, it is reduced to 3.1 hours *Renally impaired patients*: The pharmacokinetics of the drug were similar in patients with mild impairment (creatinine clearance higher than 40 ml/min) and healthy volunteers. Patients with moderate renal impairment had a 3-fold increase in half-life and 70 % decrease in clearance compared to healthy volunteers. Patients on haemodialysis (creatinine clearance less than 7 ml/min) given a single oral 10 mg dose of cetirizine had a 3-fold increase in half-life and a 70 % decrease in clearance compared to normal. Cetirizine was poorly cleared by haemodialysis. Dosing adjustment is necessary in patients with moderate or severe renal impairment (see section 4.2). *Hepatically impaired patients*: Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of cetirizine as a single dose had a 50 % increase in half-life along with a 40 % decrease in clearance compared to healthy subjects. Dosing adjustment is only necessary in hepatically impaired patients if concomitant renal impairment is present.5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6.1 List of excipients **Capsule contents** Macrogol 600 Potassium Hydroxide 43% w/w Povidone K30 Purified water **Capsule shell** Gelatin Sorbitol (E420) Glycerol Purified Water Lecithin Medium chain triglycerides Black ink **Components of black printing ink.** Propylene Glycol Black iron oxide (E172) Polyvinyl Acetate Phthalate Macrogol 400 Ammonium Hydroxide6.2 Incompatibilities Not applicable.6.3 Shelf life 36 months6.4 Special precautions for storage Store below 30°C.6.5 Nature and contents of container PVC/PE/PVdC blisters of 7 capsules sealed with aluminium lidding foil, packed into cardboard cartons.6.6 Special precautions for disposal and other handling No special requirements for disposal.