Serc - Product Informatio
|Ingredients:||Betahistine dihydrochloride, Citric acid, Colloidal anhydrous silica, Mannitol, Microcrystalline cellulose, Talc.|
Summary Product Information
|Route of Administration||Dosage Form/Strength||Non-medicinal Ingredients|
|oral||16 mg and 24 mg tablets||citric acid, colloidal anhydrous silica, mannitol, microcrystalline cellulose, and talc|
Indications and Clinical Use
SERC (betahistine dihydrochloride) is indicated for:
- reducing the episodes of recurrent vertigo associated with Ménière’s disease.
Geriatrics (> 65 Years of Age)
Limited data from clinical studies in this patient group is available. However, as with all drugs, caution should be exercised in this patient population (see Warnings and Precautions).
Pediatrics (< 18 Years of Age)
SERC is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy (see Warnings and Precautions).
SERC is contraindicated in:
- patients with known hypersensitivity to betahistine or to any of the tablet constituents. For a complete listing, see the Dosage Forms, Composition and Packaging section.
- patients with peptic ulcer and in patients with a history of this condition (see Warnings and Precautions).
- patients with pheochromocytoma.
Warnings and Precautions
Although clinical intolerance to SERC (betahistine dihydrochloride) tablets has been shown in a relatively few patients with bronchial asthma, caution should be exercised when giving the product to asthmatic patients.
Several patients with a history of peptic ulcer have experienced an exacerbation of symptoms while using SERC. Although experiments in animals and in humans have shown that the gastrointestinal side effects associated with betahistine dihydrochloride are not related to gastric acid production, SERC is contraindicated in the presence of patients with peptic ulcer and in patients with a history of this condition.
The safety of SERC in human pregnancy has not been established. Animal studies are insufficient with respect to effects on pregnancy, embryonal / foetal development, parturition and postnatal development. The potential risk for humans is unknown. Betahistine dihydrochloride should not be used during pregnancy unless the potential benefits to the mother outweigh the potential risk to the fetus.
It is not known whether betahistine dihydrochloride is excreted in human milk. There are no animal studies on the excretion of betahistine dihydrochloride in milk. The importance of the drug to the mother should be weighed against the benefits of nursing and the potential risks for the child.
Pediatrics (< 18 Years of Age)
The safety and efficacy of SERC in pediatric patients below 18 years of age have not been evaluated, therefore its use in this population is not recommended.
Geriatrics (> 65 Years of Age)
Limited data from clinical studies suggest that a dosage adjustment is unlikely to be required in this patient group. In general, however, the risk of adverse reactions to any drug may be greater in elderly patients as they are more likely to have decreased renal and/or hepatic function, and are more likely to be taking concomitant medications. Therefore, as with all drugs, caution should be exercised in this patient population.
Effect on Ability to Drive and Use Machines
Although not studied in patients with Ménière’s disease, in clinical studies using normal healthy volunteers without Ménière’s disease, 72 mg of SERC taken three times daily for three days, had no or negligible effects on driving skills in a driving task. However, Ménière’s disease itself can negatively affect the ability to drive and use machines.
Monitoring and Laboratory Tests
There is no known interference between betahistine dihydrochloride and laboratory tests.
Adverse Drug Reaction Overview
The most common adverse reactions experienced with SERC (betahistine dihydrochloride) are nausea, dyspepsia and headache.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
|Nervous System Disorders|
* Data represent adverse events reported from 23 placebo-controlled studies where the frequency of the adverse event was reported ≥ 1% in the Betahistine group and at a frequency at least ≥ 0.5% higher than placebo.
Post-Market Adverse Drug Reactions
In addition to those events reported during clinical trials, the following undesirable effects have been reported spontaneously during post-marketing use and in scientific literature. A frequency cannot be estimated from the available data and is therefore classified as 'not known'.
Ventricular extrasystoles*, hypotension*, including orthostatic and postural hypotension, tachycardia*
Mild gastric complaints (e.g. vomiting, gastrointestinal pain, abdominal distension and bloating)
|Immune System Disorders:||Hypersensitivity reactions (e.g. anaphylaxis).|
|Nervous System Disorders:||
Somnolence*, convulsions*, paraesthesia*, confusion and hallucinations*
Skin and Subcutaneous
|Angioneurotic oedema, urticaria, skin rashes of various types, pruritus and Stevens Johnson syndrome*|
* The causal relationship between SERC and the emergence of these events has not been established.
No in vivo interaction studies have been performed. In vitro data revealed no inhibition of Cytochrome P450 enzymes.
|Betahistine Dihydrochloride||Ref||Effect||Clinical comment|
|Antihistamines||T||Efficacy of either drug affected.||Caution is recommended.|
|Drugs that inhibit monoamino-oxidase (MAO) including MAO subtype B (e.g. selegiline)||In vitro||Inhibition of betahistine dihydrochloride metabolism.||Caution is recommended when using betahistine dihydrochloride and MAO inhibitors (including MAO-B selective) concomitantly.|
Legend: C = Case Study; CT = Clinical Trial; T = Theoretical
Following administration of betahistine dihydrochloride to healthy male subjects under fed conditions, the rate of absorption was slowed down and maximum concentrations (Cmax) decreased, whereas the extent of absorption (AUCinf) was not affected by food.
Interactions with herbal products have not been established.
Interactions with laboratory tests have not been established.
Dosage and Administration
Mild gastric complaints (e.g. vomiting, gastrointestinal pain, abdominal distension and bloating), have been observed. These can normally be minimized or eliminated by taking the dose during meals or by lowering the dose.
SERC is highly metabolized primarily by the liver. No pharmacokinetic data are available in patients with hepatic impairment. Caution is advised with use of SERC in this population.
Recommended Dose and Dosage Adjustment
The usual daily dosage range is 24 to 48 mg administered orally in divided doses.
Three Times Daily Dosing
16 mg tablets: ½ to 1 tablet three times daily.
Twice Daily Dosing
24 mg tablets: 1 tablet twice daily.
If a dose is missed, the missed dose should not be taken. The next dose should be taken at the usual time. A double dose should never be taken to make up for a forgotten dose.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
A few overdose cases (up to 640 mg), with mild to moderate symptoms of nausea, dry mouth, dyspepsia, abdominal pain and somnolence have been reported. Presumably, more serious complications (e.g. convulsion, pulmonary or cardiac complications) may occur in cases of intentional overdose of SERC (betahistine dihydrochloride) above 640 mg, especially in combination with other overdosed drugs. Standard overdose protocol / supportive measures should be followed.
Action and Clinical Pharmacology
Mechanism of Action
The mechanism of action of betahistine dihydrochloride is only partly understood. There are several plausible hypotheses that are supported by animal studies and human data:
Betahistine dihydrochloride affects the histaminergic system: Betahistine dihydrochloride acts both as a partial histamine H1-receptor agonist and histamine H3-receptor antagonist in neuronal tissue, and has negligible H2-receptor activity. Betahistine dihydrochloride increases histamine turnover and release by blocking presynaptic H3-receptors and inducing H3-receptor downregulation.
Betahistine dihydrochloride may increase blood flow to the cochlear region: Pharmacological testing in animals has shown that the blood circulation in the striae vascularis of the inner ear improves, probably by means of a relaxation of the precapillary sphincters of the microcirculation of the inner ear.
Betahistine dihydrochloride alters neuronal firing in the vestibular nuclei: Betahistine dihydrochloride was also found to have a dose dependent inhibiting effect on spike generation of neurons in lateral and medial vestibular nuclei.
In ten healthy male volunteers, single oral doses of 8, 16, and 32 mg of betahistine dihydrochloride given in a placebo-controlled, double-blind crossover study produced dose-related effects on the vestibular system, as measured by electronystagmography (ENG). Maximal effects on the slow nystagmus phase were found 3 to 4 hours after drug intake. Nystagmus duration was reduced by a mean value of 35% (after 8 mg), 48% (16 mg), or 59% (32 mg); all reductions were statistically significant (p<0.0005).
Eleven patients with Ménière's disease were treated in a three month, open-label study of the pharmacological effects of betahistine dihydrochloride on hearing and ENG-recorded, rotation-induced nystagmus. The study participants took one, 8 mg tablet three times a day (total daily dose, 24 mg). The speed of the quick phase of eye shift pre-treatment versus that achieved at the end of the three month treatment period was used as the parameter of effectiveness in this study. Hearing was evaluated pre- and post-treatment using three pure tone hearing levels (250, 500, 1000 Hz).
Hearing loss was less after treatment but the difference did not achieve statistical significance. At some rates of acceleration and at all rates of deceleration, there was an increase in the mean eye shift per second; this increase reached statistical significance in six of the 12 tests.
The pharmacokinetic profile of betahistine dihydrochloride was studied in six healthy male volunteers. Tablets containing 8 mg of radio-labelled betahistine dihydrochloride were administered to the subjects following an overnight fast, 30 minutes before a standard breakfast. Urine was collected for at least 56 hours after dosing, and five blood samples were drawn from each volunteer at 1, 2, 3, 8, and 25 hours for the first two volunteers, and at 1, 2, 3, 5.5, and 8 hours for the next four subjects.
Total urinary excretion of the radio-label was 90.7%, and the urinary half life was 3.5 hours. More than 85% of the administered dose was excreted in the urine within 24 hours. Only one primary urinary metabolite was identified - 2-pyridylacetic acid. Maximum plasma levels of radioactivity were attained by the 1 hour sampling time; the plasma half life of the radio-label was 3.4 hours.
Orally administered betahistine dihydrochloride is readily and almost completely absorbed from all parts of the gastro- intestinal tract. Under fed conditions Cmax is lower compared to fasted conditions. However, total absorption of betahistine dihydrochloride is similar under both conditions, indicating that food intake only slows down the absorption of betahistine dihydrochloride.
The percentage of betahistine dihydrochloride that is bound by blood plasma proteins is less than 5%.
After absorption, betahistine dihydrochloride is rapidly and almost completely metabolized into 2-pyridylacetic acid (2-PAA; which has no pharmacological activity). After oral administration of betahistine dihydrochloride the plasma (and urinary) levels of betahistine dihydrochloride are very low. Pharmacokinetic analyses are therefore based on 2-PAA measurements in plasma and urine. The plasma concentration of 2-PAA reaches its maximum 1 hour after intake and declines with a half-life of about 3.5 hours.
2-PAA is readily excreted in the urine. In the dose range between 8 and 48 mg, about 85% of the original dose is recovered in the urine. Renal or fecal excretion of betahistine dihydrochloride itself is of minor importance.
Recovery rates are constant over the oral dose range of 8 to 48 mg indicating that the pharmacokinetics of betahistine dihydrochloride are linear, and suggesting that the involved metabolic pathway is not saturated.
Special Populations and Conditions
SERC (betahistine dihydrochloride) is not recommended for use in children below 18 years of age (see Warnings and Precautions).
Limited data from clinical studies in this patient group is available, however, as with all drugs, caution should be exercised in this patient population (see Warnings and Precautions).
No gender related pharmacokinetic differences have been observed in adult patients studied.
Pharmacokinetic differences due to race have not been identified.
No pharmacokinetic data are available in patients with hepatic impairment.
No pharmacokinetic data are available in patients with renal impairment.
No data is available on genetic polymorphism.
Storage and Stability
Store tablets at controlled room temperature (15 to 30 °C). Keep in a tightly closed container to protect from moisture.
Keep in a safe place out of the sight and reach of children.
Dosage Forms, Composition and Packaging
SERC (betahistine dihydrochloride) tablets are formulated for oral administration containing betahistine dihydrochloride and are available in two strengths: 16 mg and 24 mg.
SERC 16 mg tablets are supplied as round, biconvex, scored, white to almost white tablets with bevelled edges and one side inscribed with 267 on either side of the score. The diameter of the tablet is 8.5 mm. The tablet can be divided into equal halves. The tablets are individually blister packaged and are provided in boxes of 100.
SERC 24 mg tablets are supplied as round, biconvex, scored, white to almost white tablets with bevelled edges and one side inscribed with 289 on either side of the score. The diameter of the tablet is 10 mm. The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses. The tablets are individually blister packaged and are provided in boxes of 100.
Listing of Non-Medicinal Ingredients
Each SERC 16 mg tablet contains 16 mg of betahistine dihydrochloride with the following non-medicinal ingredients: citric acid, colloidal anhydrous silica, mannitol, microcrystalline cellulose, and talc.
Each SERC 24 mg tablet contains 24 mg of betahistine dihydrochloride with the following non-medicinal ingredients: citric acid, colloidal anhydrous silica, mannitol, microcrystalline cellulose, and talc.