Actions of Zotacet MD in details
Pharmacology: Zotacet MD is used in the treatment of allergy and acts by competing with histamine for H1-receptor sites on effector cells. It antagonizes, in varying degrees, most of the pharmacological effects of histamine, including urticaria and pruritus. Also, the anticholinergic action of Zotacet MD provides a drying effect on the nasal mucosa. Zotacet MD has been shown to cause mild bronchodilation and thereby blocking histamine-induced bronchoconstriction in asthmatic patients. Due to its inhibition of late-phase eosinophil recruitment after local allergen challenge, Zotacet MD has been shown to be more effective in higher doses than other antihistamines in reducing the symptoms of pollen-induced asthma. Zotacet MD has minimal anticholinergic activity by preventing responses to acetylcholine that are mediated via muscarinic receptors.
Pharmacokinetics: After oral administration, Zotacet MD is well absorbed. Food may delay the rate, but not the extent of Zotacet MD absorption. Protein-binding of Zotacet MD is 93%. Antihistamines are usually metabolized by the hepatic cytochrome P-450 system while a certain percentage is metabolized by the kidney. However, Zotacet MD is minimally metabolized and excreted unchanged primarily through the kidneys. The t½ of Zotacet MD is almost 8 hrs. For dialysis patients, the t½ is almost 20 hrs whereas children require between 4.1-6 hrs. Peak concentration of Zotacet MD is achieved in 1 hr. Approximately 60% of the total dose administered is excreted unchanged in urine within 24 hrs and about 10% is excreted in feces. For patients with moderate renal impairment, the clearance is decreased by 70% compared to normal subjects.
How should I take Zotacet MD?
Use Zotacet MD only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.
To use the eye drops:
- Wash your hands first with soap and water.
- Shake the bottle well before each use.
- Tilt your head back and, pressing your finger gently on the skin just beneath the lower eyelid, pull the lower eyelid away from the eye to make a space. Drop the medicine into this space.
- Let go of the eyelid and gently close your eye. Do not blink. Keep the eye closed and apply pressure to the inner corner of your eye with your finger for 1 or 2 minutes to allow the medicine to be absorbed by the eye.
- If you think you did not get the drop of medicine into your eye properly, use another drop.
- To keep the medicine as germ-free as possible, do not touch the applicator tip to any surface (including the eye). Keep the bottle tightly closed.
If you are wearing contact lenses, remove them before putting the drops in your eyes. Wait at least 10 minutes after using Zotacet MD before putting your contact lenses back in. Do not wear contact lenses if your eyes are red.
Dosing
The dose of Zotacet MD will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Zotacet MD. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For ophthalmic dosage form (eye drops):
- For treatment of itching of the eye caused by allergic conjunctivitis:
- Adults and children 2 years of age and older—Put one drop in each affected eye 2 times a day.
- Children younger than 2 years of age—Use and dose must be determined by your doctor.
- For treatment of itching of the eye caused by allergic conjunctivitis:
Missed Dose
If you miss a dose of Zotacet MD, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.
Storage
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Zotacet MD may also be stored in a cool, dry place.
Zotacet MD administration
For topical ophthalmic use only. Use single-use containers immediately after opening; single-use containers can be used to dose both eyes. Wash hands before use. Do not touch dropper tip to eyelids, surrounding areas, or any surface. Remove contact lenses prior to administration. After instilling drops, wait ≥10 minutes before inserting contact lenses. Do not wear contacts lenses if eyes are red. Discard single-use container and remaining contents immediately after use.
Zotacet MD pharmacology
Mechanism of Actions: Zotacet MD, a human metabolite of hydroxyzine, is an antihistamine; its principal effects are mediated via selective inhibition of peripheral H1 receptors. The antihistaminic activity of Zotacet MD has been clearly documented in a variety of animal and human models. In vivo and ex vivo animal models have shown negligible anticholinergic and antiserotonergic activity. In clinical studies, however, dry mouth was more common with Zotacet MD than with placebo. In vitro receptor binding studies have shown no measurable affinity for other than H1 receptors. Autoradiographic studies with radiolabeled Zotacet MD in the rat have shown negligible penetration into the brain. Ex vivo experiments in the mouse have shown that systemically administered Zotacet MD does not significantly occupy cerebral H1 receptors.
Pharmacokinetics:
Absorption: Zotacet MD was rapidly absorbed with a time to maximum concentration (Tmax) of approximately 1 hour following oral administration of tablets or syrup in adults. Comparable bioavailability was found between the tablet and syrup dosage forms. When healthy volunteers were administered multiple doses of Zotacet MD (10 mg tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311 ng/mL was observed. No accumulation was observed. Zotacet MD pharmacokinetics were linear for oral doses ranging from 5 to 60 mg. Food had no effect on the extent of Zotacet MD exposure (AUC) but Tmax was delayed by 1.7 hours and Cmax was decreased by 23% in the presence of food.
Distribution: The mean plasma protein binding of Zotacet MD is 93%, independent of concentration in the range of 25-1000 ng/mL, which includes the therapeutic plasma levels observed.
Metabolism: A mass balance study in 6 healthy male volunteers indicated that 70% of the administered radioactivity was recovered in the urine and 10% in the feces. Approximately 50% of the radioactivity was identified in the urine as unchanged drug. Most of the rapid increase in peak plasma radioactivity was associated with parent drug, suggesting a low degree of first-pass metabolism. Zotacet MD is metabolized to a limited extent by oxidative O-dealkylation to a metabolite with negligible antihistaminic activity. The enzyme or enzymes responsible for this metabolism have not been identified.
Elimination: The mean elimination half-life in 146 healthy volunteers across multiple pharmacokinetic studies was 8.3 hours and the apparent total body clearance for Zotacet MD was approximately 53 mL/min.
Interaction Studies
Pharmacokinetic interaction studies with Zotacet MD in adults were conducted with pseudoephedrine, antipyrine, ketoconazole, erythromycin and azithromycin. No interactions were observed. In a multiple dose study of theophylline (400 mg once daily for 3 days) and Zotacet MD (20 mg once daily for 3 days), a 16% decrease in the clearance of Zotacet MD was observed. The disposition of theophylline was not altered by concomitant Zotacet MD administration.
Special Populations
Pediatric Patients: In pediatric patients aged 2 to 5 years who received 5 mg of Zotacet MD, the mean Cmax was 660 ng/mL. Based on cross study comparisons, the weight normalized, apparent total body clearance was 81-111% greater and the elimination half life was 33 to 41% shorter in the pediatric population than in adults. In pediatric patients aged 6 to 23 months who received a single dose of 0.25 mg/kg Zotacet MD oral solution (mean dose 2.3 mg), the mean Cmax was 390 ng/mL. Based on cross-study comparisons, the weight-normalized, apparent total body clearance was 304% greater and the elimination half-life was 63% shorter in this pediatric population compared to adults. The average AUC(0-t) in children 6 months to <2 years of age receiving the maximum dose of Zotacet MD solution (2.5 mg twice a day) is expected to be two-fold higher than that observed in adults receiving a dose of 10 mg Zotacet MD tablets once a day.
Effect of Gender: The effect of gender on Zotacet MD pharmacokinetics has not been adequately studied.
Effect of Race: No race-related differences in the kinetics of Zotacet MD have been observed.
Pharmacodynamics: Zotacet MD hydrochloride at doses of 5 and 10 mg strongly inhibited the wheal and flare caused by intradermal injection of histamine in 19 pediatric volunteers (aged 5 to 12 years) and the activity persisted for at least 24 hours. In a 35-day study in children aged 5 to 12, no tolerance to the antihistaminic (suppression of wheal and flare response) effects of Zotacet MD hydrochloride was found. In 10 infants 7 to 25 months of age who received 4 to 9 days of Zotacet MD in an oral solution (0.25 mg/kg bid), there was a 90% inhibition of histamine-induced (10 mg/mL) cutaneous wheal and 87% inhibition of the flare 12 hours after administration of the last dose. The clinical relevance of this suppression of histamine-induced wheal and flare response on skin testing is unknown.
The effects of intradermal injection of various other mediators or histamine releasers were also inhibited by Zotacet MD, as was response to a cold challenge in patients with cold-induced urticaria. In mildly asthmatic subjects, Zotacet MD hydrochloride at 5 to 20 mg blocked bronchoconstriction due to nebulized histamine, with virtually total blockade after a 20-mg dose. In studies conducted for up to 12 hours following cutaneous antigen challenge, the late phase recruitment of eosinophils, neutrophils and basophils, components of the allergic inflammatory response, was inhibited by Zotacet MD hydrochloride at a dose of 20 mg.
In four clinical studies in healthy adult males, no clinically significant mean increases in QTc were observed in Zotacet MD hydrochloride treated subjects. In the first study, a placebo-controlled crossover trial, Zotacet MD hydrochloride was given at doses up to 60 mg per day, 6 times the maximum clinical dose, for 1 week, and no significant mean QTc prolongation occurred. In the second study, a crossover trial, Zotacet MD hydrochloride 20 mg and erythromycin (500 mg every 8 hours) were given alone and in combination. There was no significant effect on QTc with the combination or with Zotacet MD hydrochloride alone. In the third trial, also a crossover study, Zotacet MD hydrochloride 20 mg and ketoconazole (400 mg per day) were given alone and in combination. Zotacet MD hydrochloride caused a mean increase in QTc of 9.1 msec from baseline after 10 days of therapy. Ketoconazole also increased QTc by 8.3 msec. The combination caused an increase of 17.4 msec, equal to the sum of the individual effects. Thus, there was no significant drug interaction on QTc with the combination of Zotacet MD hydrochloride and ketoconazole. In the fourth study, a placebo-controlled parallel trial, Zotacet MD hydrochloride 20 mg was given alone or in combination with azithromycin (500 mg as a single dose on the first day followed by 250 mg once daily). There was no significant increase in QTc with Zotacet MD hydrochloride 20 mg alone or in combination with azithromycin.
In a four-week clinical trial in pediatric patients aged 6 to 11 years, results of randomly obtained ECG measurements before treatment and after 2 weeks of treatment showed that Zotacet MD hydrochloride 5 or 10 mg did not increase QTc versus placebo. In a one week clinical trial (N=86) of Zotacet MD hydrochloride syrup (0.25 mg/kg bid) compared with placebo in pediatric patients 6 to 11 months of age, ECG measurements taken within 3 hours of the last dose did not show any ECG abnormalities or increases in QTc interval in either group compared to baseline assessments. Data from other studies where Zotacet MD hydrochloride was administered to patients 6-23 months of age were consistent with the findings in this study.
The effects of Zotacet MD hydrochloride on the QTc interval at doses higher than 10 mg have not been studied in children less than 12 years of age.
In a six-week, placebo-controlled study of 186 patients (aged 12 to 64 years) with allergic rhinitis and mild to moderate asthma, Zotacet MD hydrochloride 10 mg once daily improved rhinitis symptoms and did not alter pulmonary function. In a two-week, placebo-controlled clinical trial, a subset analysis of 65 pediatric (aged 6 to 11 years) allergic rhinitis patients with asthma showed Zotacet MD hydrochloride did not alter pulmonary function. These studies support the safety of administering Zotacet MD hydrochloride to pediatric and adult allergic rhinitis patients with mild to moderate asthma.
Clinical Studies: Multicenter, randomized, double-blind, clinical trials comparing Zotacet MD 5 to 20 mg to placebo in patients 12 years and older with perennial allergic rhinitis were conducted in the United States. Two of these showed significant reductions in symptoms of perennial allergic rhinitis for up to 8 weeks in duration. Two 4-week multicenter, randomized, double-blind clinical trials comparing Zotacet MD 5 to 20 mg to placebo in patients with chronic idiopathic urticaria were also conducted and showed significant improvement in symptoms of chronic idiopathic urticaria. In general, the 10-mg dose was more effective than the 5-mg dose and the 20-mg dose gave no added effect. Some of these trials included pediatric patients aged 12 to 16 years. In addition, four multicenter, randomized, placebo-controlled, double-blind 2-4 week trials in 534 pediatric patients aged 6 to 11 years with seasonal allergic rhinitis were conducted in the United States at doses up to 10 mg.
References
- DailyMed. "CETIRIZINE HYDROCHLORIDE; PSEUDOEPHEDRINE HYDROCHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Cetirizine Hydrochloride: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Cetirizine: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
