Synactiv

Levocetirizine dihydrochloride, betamethasone sodium phosphate USP.

Each film-coated tablet contains: Levocetirizine dihydrochloride 5 mg and Betamethasone (as sodium phosphate) USP 1 mg.

Pharmacology: Levocetirizine: Pharmacodynamics: Levocetirizine at doses of 2.5 mg and 5 mg inhibited the skin wheal and flare caused by the intradermal injection of histamine. The activity persists for 24 hours. In contrast, dextrocetirizine exhibited no clear change in the inhibition of the wheal and flare reaction.
Mechanism of Action: Levocetirizine, the active enantiomer of cetirizine, is an anti-histamine; its principal effects are mediated via selective inhibition of H1 receptors. The antihistaminic activity of Levocetirizine has been documented in a variety of animal and human models. In vitro binding studies revealed that Levocetirizine has an affinity for the human H1-receptor 2-fold higher than that of cetirizine. The clinical relevance of this finding is unknown.
Pharmacokinetics: Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 hour after administration of an oral tablet with peak plasma concentrations reaching 270 ng/mL and 308 ng/mL following a single and a repeated 5 mg once daily dose, respectively. The extent of absorption is dose independent and is not altered by food, but the peak concentration is reduced and delayed.
Distribution: The mean plasma protein binding of Levocetirizine in vitro ranged from 91 to 92%, independent of concentration in the range of 90-5000 ng/mL, which includes the therapeutic plasma levels observed. Following oral dosing, the average apparent volume of distribution is approximately 0.4 L/kg, representative of distribution in total body water.
Metabolism: The extent of metabolism of levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of hepatic drug metabolizing enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N and O-dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involves multiple and/or unidentified CYP isoforms.
Elimination: The plasma half-life in adult healthy subjects was about 8 to 9 hours after administration of oral tablets and oral solution, and the mean oral total body clearance for Levocetirizine was approximately 0.63 mL/kg/min. The major route of excretion of levocetirizine and its metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion. Renal clearance of Levocetirizine correlates with that of creatinine clearance. In patients with renal impairment the clearance of Levocetirizine is reduced.
Renal Impairment: Levocetirizine exposure (AUC) exhibited 1.8-, 3.2-, 4.3-, and 5.7-fold increase in mild, moderate, severe, renal impaired, and end-stage renal disease patients, respectively, compared to healthy subjects. The corresponding increases of half-life estimates were 1.4-, 2.0-, 2.9-, and 4-fold, respectively. The total body clearance of Levocetirizine after oral dosing was correlated to the creatinine clearance and was progressively reduced based on severity of renal impairment.
Hepatic Impairment: Levocetirizine has not been studied in patients with hepatic impairment. The non-renal clearance (indicative of hepatic contribution) was found to constitute about 28% of the total body clearance in healthy adult subjects after oral administration. As Levocetirizine is mainly excreted unchanged by the kidney, it is unlikely that the clearance of Levocetirizine is significantly decreased in patients with solely hepatic impairment.
Betamethasone: Betamethasone is a moderately potent glucocorticoid steroid with anti-inflammatory and immunosuppressive properties. It acts primarily through by inhibiting the release of various cytokines. Like other corticosteroids, Betamethasone is readily absorbed from the gastrointestinal tract and rapidly distributed to all body tissues. Corticosteroids cross the placenta to varying degrees and may be excreted in small amounts in breast milk. Most corticosteroids in the circulation are extensively bound to plasma proteins, mainly to globulin and less so to albumin. The corticosteroid-binding globulin has high affinity but low binding capacity. The synthetic corticosteroids, including Betamethasone, are less extensively protein bound than hydrocortisone. They also tend to have longer half-lives. Corticosteroids are metabolized mainly in the liver but also in other tissues and are excreted in the urine. The slower metabolism of synthetic corticosteroids with their lower protein-binding affinity may account for their increased potency compared with the natural corticosteroids.

Indicated for the short term treatment of urticaria and intermittent perennial or persistent allergic rhinitis.

Adults and adolescents 15 years of age and older: One tablet, once daily. Or as prescribed by the physician.
Renal Impairment: No dosage adjustment is needed in patients with mild renal impairment. In patients with moderate renal impairment (creatinine clearance 30-49 mL/min) the dose should be adjusted to one tablet every two (2) days. The fixed dose combination of Levocetirizine plus Betamethasone is contraindicated in patients with severe renal failure.
Hepatic Impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. The fixed dose combination of Levocetirizine plus Betamethasone is contraindicated in patients with severe renal failure.

Hypersensitivity to Levocetirizine or Betamethasone, severe renal impairment (creatinine clearance <10mL/min), severe hepatic impairment, systemic infections (unless specific anti-infective therapy is employed). Pregnancy and Lactation.

Levocetirizine: In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with levocetirizine. Concurrent use of Levocetirizine with other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.
Betamethasone: Caution is advised with the use of corticosteroids in patients who have suffered a recent myocardial infarction because of the risk of myocardial rupture. Caution is advised on the use of corticosteroids in patients with hypothyroidism. Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicemia and tuberculosis may be masked and may reach an advanced stage before being recognized. Adrenal cortical atrophy develops during prolonged corticosteroid therapy and may persist for years after stopping treatment. Abrupt withdrawal of the fixed dose combination of Levocetirizine 5mg plus Betamethasone 1mg once daily after 5-7 days of treatment is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In patients who have received the fixed dose combination of levocetirizine 5mg plus betamethasone 1mg once daily for more than three weeks, withdrawal should not be abrupt. Dose reduction should be slower to allow the HPA-axis to recover. Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary: A. Osteoporosis (post-menopausal females are particularly at risk). B. Hypertension or congestive heart failure. C. Existing or previous history of severe affective disorders (especially previous steroid psychosis). D. Diabetes mellitus (or a family history of diabetes). E. History of tuberculosis. F. Glaucoma (or a family history of glaucoma). G. Previous corticosteroid-induced myopathy. H. Liver failure-blood levels of corticosteroid may be increased, (as with other drugs which are metabolized in the liver). I. Renal insufficiency. J. Epilepsy. K. Peptic ulceration. Potentially severe psychiatric adverse reactions may occur with systemic steroids. The common adverse effects of systemic corticosteroids may be associated with more serious consequences in the elderly, especially osteoporosis, hypertension, hypokalemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

The fixed dose combination of Levocetirizine plus Betamethasone is not recommended in pregnant women or nursing mothers.

Levocetirizine: In five hundred and ten atopic children aged between 12-24 months who received 0.125 mg/kg Levocetirizine twice daily for 18 months the following adverse reactions were observed in Levocetirizine (L) and placebo (P) treated infants; Wheezing: L 4.7%, P 7.5%. Atopic Dermatitis: L 1.2%, P 2.4%. Gastroenteritis: L 0.8%, P 2.0%. Cough: L 1.6%, P 0.8%. Bronchopneumonia: L 1.6%, P 0.4%. Febrile Convulsion: L 1.6%, P 0.0%. Urticaria: L 0.4%, P 1.2%. Chronic Bronchitis: L 0.0%, P 1.2%. Pneumonia: L 0.8%, P 0.0%. The frequency of adverse events, serious adverse events, medication attributed adverse events and adverse events that led to permanent discontinuation of study medication were not significantly different from placebo. A total of 243 pediatric patients 6 to 12 years of age received Levocetirizine 5 mg once daily in two short-term placebo controlled double-blind trials. The mean age of the patients was 9.8 years, 79 (32%) were between 6-8 years of age. The adverse reactions that were reported in greater than or equal to 2% of subjects aged 6-12 years exposed to Levocetirizine 5 mg in placebo-controlled clinical trials and that were more common with Levocetirizine (L) than placebo (P) were as follows; Pyrexia: L 4%, P 2%. Cough: L 3%, P (<1%). Somnolence: L 3%, P <1%. Epistaxis: L 2%, P <1%.
Laboratory Test Abnormalities: Elevations of blood bilirubin and transaminases were reported in <1% of patients in the clinical trials. The elevations were transient and did not lead to discontinuation in any patient. In addition to the adverse reactions reported during clinical trials and listed previously, adverse events have also been identified during post-approval use of Levocetirizine in adults and or children. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse events of hypersensitivity and anaphylaxis, angioneurotic edema, fixed drug eruption, pruritus, rash, and urticaria, convulsion, aggression and agitation, visual disturbances, palpitations, dyspnea, nausea, hepatitis, and myalgia have been reported. Besides these events reported under treatment with Levocetirizine, other potentially severe adverse events have been reported from the post-marketing experience with cetirizine. Since Levocetirizine is the principal pharmacologically active component of cetirizine, one should take into account the fact that the following adverse events could also potentially occur under treatment with Levocetirizine: hallucinations, suicidal ideation, orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, and still birth.
Betamethasone: Endocrine/metabolic: Suppression of the hypothalamic-pituitary-adrenal axis, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhea. Cushingoid facies, hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy. Negative protein, nitrogen and calcium balance. Increased appetite. Hyperhydrosis. Increased high-density lipoprotein and low-density lipoprotein concentrations in the blood.
Anti-inflammatory and immunosuppressive effects: Increased susceptibility to and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis.
Musculoskeletal: Osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture, proximal myopathy.
Fluid and electrolyte disturbance: Sodium and water retention, hypertension, potassium loss, hypokalaemic alkalosis.
Neuropsychiatric: A wide range of psychiatric reactions including affective disorder (such as irritable, euphoric, depressed and labile mood and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations and aggravation of schizophrenia), behavioral disturbances, irritability, anxiety, sleep disturbances and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common any may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to the 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown. Aggravation of epilepsy.
Ophthalmic: Increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, corneal or scleral thinning and exacerbation of ophthalmic viral or fungal diseases.
Cardiac: Myocardial rupture following recent myocardial infarction.
Gastrointestinal: Abdominal distension, esophageal ulceration, nausea, dyspepsia, peptic ulceration with perforation and haemorrhage, acute pancreatitis, candidiasis.
Dermatological: Impaired healing, skin atrophy, bruising, telangiectasia, striae, acne.
General: Hypersensitivity including anaphylaxis has been reported. Leucocytosis. Thrombo-embolism. Malaise. Hiccups.
Withdrawal symptoms and signs: Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. A 'withdrawal syndrome' may also occur including; fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

Levocetirizine: In vitro data indicate that Levocetirizine is unlikely to produce pharmacokinetic interactions through inhibition or induction of liver drug-metabolizing enzymes. No in vivo drug-drug interaction studies have been performed with Levocetirizine. Drug interaction studies have been performed with racemic cetirizine. Pharmacokinetic interaction studies performed with racemic cetirizine demonstrated that cetirizine did not interact with antipyrine, pseudoephedrine, erythromycin, azithromycin, ketoconazole, and cimetidine. There was a small decrease (~16%) in the clearance of cetirizine caused by a 400 mg dose of theophylline. It is possible that higher theophylline doses could have a greater effect. Ritonavir increased the plasma AUC of cetirizine by about 42% accompanied by an increase in half-life (53%) and a decrease in clearance (29%) of cetirizine. The disposition of ritonavir was not altered by concomitant cetirizine administration.
Betamethasone: Steroids may reduce the effects of anti-cholinesterase's in myasthenia gravis cholecystographic X-ray media and non-steroidal anti-inflammatory agents. Rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, aminoglutethimide and ephedrine enhance the metabolism of corticosteroids; thus the corticosteroid therapeutic effect may be reduced. The desired effects of hypoglycemic agents (including insulin), anti-hypertensive's and diuretics are antagonized by corticosteroids, and the hypokalemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced. The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication. The risk of hypokalemia is increased with theophylline, ulcer healing drugs such as carbenoxolone and antifungals such as amphotericin B. Increased toxicity may result if hypokalemia occurs in patients on cardiac glycosides. Ritonavir and oral contraceptives may result in increased plasma concentrations or corticosteroids. The effect of corticosteroids may be reduced for 3-4 days after mifepristone. The growth promoting effect of somatropin may be inhibited by corticosteroids. An increase in the incidence of gastrointestinal bleeding may occur if NSAIDS are taken concomitantly with corticosteroids. Corticosteroids may antagonize the effects of neuromuscular blocking drugs such as vecuronium.

Store at temperatures not exceeding 30°C.

Antihistamines & Antiallergics

R06AE09 - levocetirizine ; Belongs to the class of piperazine derivatives used as systemic antihistamines.

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