Synactiv

Levocetirizine dihydrochloride, betamethasone sodium phosphate.

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

Antihistamine/Corticosteroids.
Pharmacology: Pharmacodynamics: Levocetirizine: Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors.
Binding studies revealed that levocetirizine has high affinity for human H1-receptors (Ki = 3.2 nmol/l). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/l). Levocetirizine dissociates from H1-receptors with a half-life of 115 ± 38 min.
After single administration, levocetirizine shows a receptor occupancy of 90% at 4 hours and 57% at 24 hours.
Betamethasone: Betamethasone provides potent anti-inflammatory and antiallergic effects in the treatment of corticosteroid-responsive disorders.
Pharmacokinetics: Levocetirizine: The pharmacokinetics of levocetirizine are linear with dose- and time-independent with low inter-subject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.
Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 h after dosing. Steady state is achieved after two days. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg o.d. dose, respectively. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.
Distribution: No tissue distribution data are available in humans, neither concerning the passage of levocetirizine through the blood-brain-barrier. In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in the CNS compartment.
In humans, levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.
Biotransformation: 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 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 involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose.
Due to its low metabolism and absence of metabolic inhibition potential, the interaction of levocetirizine with other substances, or vice-versa, is unlikely.
Elimination: The plasma half-life in adults is 7.9 ± 1.9 hours. The half-life is shorter in small children.
The mean apparent total body clearance in adults is 0.63 ml/min/kg. The major route of excretion of levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.
Betamethasone: Absorption: The vast majority of corticosteroids, including betamethasone, are absorbed from the gastrointestinal tract.
Biotransformation: Corticosteroids are metabolised mainly in the liver but also in the kidney, and are excreted in the urine.
Synthetic corticosteroids, such as prednisolone, have increased potency when compared to the natural corticosteroids, due to their slower metabolism and lower protein-binding affinity.

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.

Levocetirizine: Symptoms: Symptoms of overdose may include drowsiness in adults. In children, agitation and restlessness may initially occur, followed by drowsiness.
Management of overdoses: There is no known specific antidote to levocetirizine.
Should overdose occur, symptomatic or supportive treatment is recommended.
Gastric lavage may be considered shortly after ingestion of the drug.
Levocetirizine is not effectively removed by haemodialysis.
Betamethasone: Symptoms: Acute overdosage with glucocorticosteroids, including betamethasone, is not expected to lead to a life-threatening situation. Except at the most extreme dosages, a few days of excessive glucocorticosteroid dosing is unlikely to produce harmful results in the absence of specific contraindications, such as in patients with diabetes mellitus, glaucoma, or active peptic ulcer, or in patients on medications such as digitalis, coumarin-type anti-coagulants or potassium-depleting diuretics.
Treatment: In the event of overdosage, consultation with a poison control center should be considered. Consider standard measures to remove any unabsorbed drug, e.g. gastric lavage. Otherwise complications resulting from the metabolic effects of the corticosteroid or from deleterious effects of the basic or concomitant illnesses or resulting from drug interactions should be handled as appropriate.

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: Precaution is recommended with concurrent intake of alcohol.
Caution should be taken in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention.
Caution should be taken in patients with epilepsy and patients at risk of convulsion as levocetirizine may cause seizure aggravation.
Response to allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pruritus may occur when levocetirizine is stopped even if those symptoms were not present before treatment initiation. The symptoms may resolve spontaneously. In some cases, the symptoms may be intense and may require treatment to be restarted. The symptoms should resolve when the treatment is restarted.
Betamethasone: Dosage adjustments may be required with remission or exacerbation of the disease process, the patient's individual response to therapy and exposure of the patient to emotional or physical stress such as serious infection, surgery or injury. Monitoring may be necessary for up to one year following cessation of long-term or high dose corticosteroid therapy.
Corticosteroids may mask some signs of infection, and new infections may appear during use. When corticosteroids are used, decreased resistance and inability to localize infection may occur.
Prolonged corticosteroid use may produce posterior sub capsular cataracts (especially in children), glaucoma with possible damage to the optic nerves, and may enhance secondary ocular infections due to fungi or viruses.
Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be considered. All corticosteroids increase calcium excretion.
While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients receiving corticosteroids, especially high doses, because of possible hazards of neurological complications and lack of antibody response. However, immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison disease. Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to obtain medical advice.
This is of particular importance in children.
Corticosteroid therapy in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for management in conjunction with an appropriate anti-tuberculous regimen.
If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary since reactivation of the disease may occur. During prolonged corticosteroid therapy, patients should receive chemoprophylaxis. If rifampin is used in a chemoprophylactic program, its enhancing effect on metabolic hepatic clearance of corticosteroids should be considered; adjustment in corticosteroid dosage may be required.
The lowest possible dose of corticosteroid should be used to control the condition under treatment; when dosage reduction is possible, it should be gradual.
Drug-induced secondary adrenocortical insufficiency may result from too rapid corticosteroid withdrawal and may be minimized by gradual dosage reduction. Such relative insufficiency may persist for months after discontinuation of therapy; therefore, if stress occurs during that period, corticotherapy should be reinstituted. If the patient is receiving corticosteroids already, dosage may have to be increased. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticosteroid should be administered concurrently. Corticosteroid effect is enhanced in patients with hypothyroidism or in those with cirrhosis. Cautious use of corticosteroids is advised in patients with ocular herpes simplex because of possible corneal perforation.
Psychic derangements may appear with corticosteroid therapy. Existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.
Corticosteroids should be used with caution in: nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess, or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; and myasthenia gravis. Since complications of glucocorticosteroid treatment are dependent on dose, size and duration of treatment, a risk/benefit decision must be made with each patient.
Since corticosteroid administration can disturb growth rates and inhibit endogenous corticosteroid production in infants and children, the growth and development of these patients receiving prolonged therapy should be followed carefully.
Corticosteroids may alter the motility and number of spermatozoa in some patients.

Levocetirizine: There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of levocetirizine in pregnant women. However, for cetirizine, the racemate of levocetirizine, a large amount of data (more than 1000 pregnancy outcomes) on pregnant women indicate no malformative or feto / neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/fetal development, parturition or postnatal development.
Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human. Therefore, the excretion of levocetirizine in human milk is likely. Adverse reactions associated with levocetirizine may be observed in breastfed infants. Therefore, caution should be exercised when prescribing levocetirizine to lactating women.
Betamethasone: Since controlled human reproduction studies have not been done with corticosteroids, the use of Betamethasone during pregnancy, in nursing mothers or women of child-bearing age requires that the possible benefits of the drug be weighed against potential hazards to mother and fetus or infant.
Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be observed carefully for signs of hypoadrenalism.

Levocetirizine: Clinical studies: In therapeutic studies in women and men aged 12 to 71 years, 15.1% of the patients in the levocetirizine 5 mg group had at least one adverse drug reaction compared to 11.3% in the placebo group. 91.6 % of these adverse drug reactions were mild to moderate.
In therapeutic trials, the dropout rate due to adverse events was 1.0% (9/935) with levocetirizine 5 mg and 1.8% (14/771) with placebo.
Clinical therapeutic trials with levocetirizine included 935 subjects exposed to the medicinal product at the recommended dose of 5 mg daily. From this pooling, following incidence of adverse drug reactions were reported at rates of 1% or greater (common: ≥1/100 to <1/10) under levocetirizine 5 mg or placebo: (See table.)

Click on icon to see table/diagram/image

Further uncommon incidences of adverse reactions (uncommon ≥1/1,000 to <1/100) like asthenia or abdominal pain were observed.
The incidence of sedating adverse drug reactions such as somnolence, fatigue, and asthenia was altogether more common (8.1%) under levocetirizine 5 mg than under placebo (3.1%).
Post-marketing experience: Adverse reactions from post-marketing experience are per System Organ Class and per frequency. The frequency is 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).
Immune system disorders: Not known: hypersensitivity including anaphylaxis.
Metabolism and nutrition disorders: Not known: increased appetite.
Psychiatric disorders: Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation, nightmare.
Nervous system disorders: Not known: convulsion, paraesthesia, dizziness, syncope, tremor, dysgeusia.
Ear and labyrinth disorders: Not known: vertigo.
Eyes disorders: Not known: visual disturbances, blurred vision.
Cardiac disorders: Not known: palpitations, tachycardia.
Respiratory, thoracic and mediastinal disorders: Not known: dyspnoea.
Gastrointestinal disorders: Not known: nausea, vomiting, diarrhoea.
Hepatobiliary disorders: Not known: hepatitis.
Renal and urinary disorders: Not known: dysuria, urinary retention.
Skin and subcutaneous tissue disorders: Not known: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria.
Musculoskeletal, connective tissues, and bone disorders: Not known: myalgia, arthralgia.
General disorders and administration site conditions: Not known: oedema.
Investigations: Not known: weight increased, abnormal liver function tests.
Description of selected adverse reactions: After levocetirizine discontinuation, pruritus has been reported.
Betamethasone: Adverse reactions to Betamethasone, which have been the same as those reported for other corticosteroids, relate both to dose and to duration of therapy.
Usually these reactions can be reversed or minimized by a reduction in dosage; this is generally preferable to withdrawal of drug treatment.
Fluid and electrolyte disturbances: sodium retention, potassium loss, hypokalemic alkalosis; fluid retention; congestive heart failure in susceptible patients; hypertension.
Musculoskeletal: muscle weakness, corticosteroid myopathy, loss of muscle mass; aggravation of myasthenic symptoms in myasthenia gravis; osteoporosis; vertebral compression fractures; aseptic necrosis of femoral and humeral heads; pathologic fracture of long bones; tendon rupture.
Gastrointestinal: peptic ulcer with possible subsequent perforation and hemorrhage; pancreatitis, abdominal distention; ulcerative esophagitis, hiccups.
Dermatologic: impaired wound healing, skin atrophy, thin fragile skin; petechiae and ecchymoses; facial erythema; increased sweating; suppressed reactions to skin tests; reactions such as allergic dermatitis, urticaria, angioneurotic edema.
Neurologic: convulsions; increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment; vertigo; headache.
Endocrine: menstrual irregularities; development of cushingoid state; suppression of fetal intrauterine or childhood growth; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness; decreased carbohydrate tolerance, manifestations of latent diabetes mellitus, increased requirements of insulin or oral hypoglycemic agents in diabetics.
Ophthalmic: posterior subcapsular cataracts; increased intraocular pressure, glaucoma; exophthalmos.
Metabolic: negative nitrogen balance due to protein catabolism.
Psychiatric: euphoria, mood swings; severe depression to frank psychotic manifestations; personality changes; hyperirritability; insomnia.
Other: anaphylactoid or hypersensitivity and hypotensive or shock-like reactions.

Levocetirizine: No interaction studies have been performed with levocetirizine (including no studies with CYP3A4 inducers); studies with the racemate compound cetirizine demonstrated that there were no clinically relevant adverse interactions (with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole and pseudoephedrine). A small decrease in the clearance of cetirizine (16%) was observed in a multiple dose study with theophylline (400 mg once a day); while the disposition of theophylline was not altered by concomitant cetirizine administration.
In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.
The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.
In sensitive patients, the concurrent administration of cetirizine or levocetirizine and alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.
Betamethasone: Concurrent use of phenobarbital, phenytoin, rifampin or ephedrine may enhance the metabolism of corticosteroids, reducing their therapeutic effects.
Patients receiving both a corticosteroid and an estrogen should be observed for excessive corticosteroid effects.
Concurrent use of corticosteroids with potassium depleting diuretics may enhance hypokalemia. Concurrent use of corticosteroids with cardiac glycosides may enhance the possibility of arrhythmias or digitalis toxicity associated with hypokalemia. Corticosteroids may enhance the potassium depletion caused by amphotericin B. In all patients taking any of these drug therapy combinations, serum electrolyte determinations, particularly potassium levels, should be monitored closely.
Concurrent use of corticosteroids with coumarin type anticoagulants may increase or decrease the anticoagulant effects, possibly requiring adjustment in dosage.
Combined effects of non-steroidal anti-inflammatory drugs or alcohol with glucocorticosteroids may result in an increased occurrence or increased severity of gastrointestinal ulceration.
Corticosteroids may decrease blood salicylate concentrations. Acetylsalicylic acid should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.
Dosage adjustments of an antidiabetic drug may be necessary when corticosteroids are given to diabetics. Concomitant glucocorticosteroid therapy may inhibit the response to somatotropin.
Laboratory Test Interactions: Corticosteroids may affect the nitroblue tetrazolium test for bacterial infection and produce false negative results.

Store at temperatures not exceeding 30°C. Protect from moisture.

Antihistamines & Antiallergics

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

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