Relax S

Uses

• * Anxiety disorder
• * Short term relief of anxiety
• * Anxiety associated with depression
• * Panic disorder, with or without agoraphobia.

Sertraline is used for Depressive illness, Obsessive-compulsive disorder, Post-traumatic stress disorder, Panic disorder

Relax S is also used to associated treatment for these conditions: Anxiety, Generalized Anxiety Disorder (GAD), Panic DisorderBinge Eating Disorder (BED), Bulimia Nervosa, Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), Obsessive Compulsive Disorder (OCD), Panic Disorder, Post Traumatic Stress Disorder (PTSD), Premenstrual Dysphoric Disorder, Social Anxiety Disorder (SAD)

How Relax S works

Alprazolam is a triazolobenzodiazepine used to treat certain anxiety and panic disorders. Alprazolam acts on benzodiazepine receptors BNZ-1 and BNZ-2. The active metabolites 4-hydroxyalprazolam acts on these receptors with 0.20 times the potency of alprazolam and alpha-hydroxyalprazolam acts on these receptors with 0.66 times the potency.

The effect of alprazolam on BNZ-1 mediates the sedation and anti-anxiety effects of the drug while the action on BNZ-2 mediates effects on memory, coordination, muscle relaxation, and anticonvulsive activity.

Alprazolam also couple with GABA-A receptors to enhance GABA binding to its receptor. This interaction mediates inhibition of the nervous system and results in a calming effect.

The molecular mechanisms as well as the clinical effects of alprazolam have both been well demonstrated, however the means by which the molecular mechanism translates to a clinical effect is still not understood.

Sertraline selectively inhibits the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane, thereby increasing serotonergic activity. This results in an increased synaptic concentration of serotonin in the CNS, which leads to numerous functional changes associated with enhanced serotonergic neurotransmission. These changes are believed to be responsible for the antidepressant action and beneficial effects in obsessive-compulsive (and other anxiety related disorders). It has been hypothesized that obsessive-compulsive disorder, like depression, is also caused by the disregulation of serotonin.

In animal studies, chronic administration of sertraline results in down-regulation of brain norepinephrine receptors. Sertraline displays affinity for sigma-1 and 2 receptor binding sites, but binds with stronger affinity to sigma-1 binding sites. In vitro, sertraline shows little to no affinity for GABA, dopaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors. It exerts weak inhibitory actions on the neuronal uptake of norepinephrine and dopamine and exhibits no inhibitory effects on the monoamine oxidase enzyme.

Dosage

Relax S dosage

Treatment should be initiated with a dose of 0.25 to 0.5 mg three times daily. Depending on the response, dose may

be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. The maximum dose should not

exceed 4 mg/day. Occasional patients with panic disorder may need as much as 10 mg a day to achieve a

successful response and in these cases periodic reassessment and consideration of dosage adjustment is required.

Dosage should be individualized for maximum beneficial effect with a lowest possible dose. If side-effects occur at

starting dose, dose may be lowered. When discontinuing therapy, dosage should be reduced gradually by no more

than 0.5 mg every three days.

In elderly patients or in patients with advanced liver disease, the usual starting dose is 0.25 mg, two or three times

daily and may be gradually increased if needed and tolerated. Safety and effectiveness of Alprazolam in individuals

below 18 years of age have not been established.

Alprazolam XR 1 should be administered once daily, preferably in the morning by patients who are on multiple dosage

regimen of Alprazolam 0.25/0.5 mg. The tablets should be taken intact, they should not be chewed, crushed, or broken.

Depressive illness:

• Adult: Initially 50 mg daily, increased if necessary by increments of 50 mg over several weeks to maximum 200 mg daily. Usual maintenance dose is 50 mg daily.
• Child and adolescent less than 18 years:Not recommended.

Obsessive-compulsive disorder:

• Adult and adolescent over 13 years: Initially 50 mg daily, increased if necessary in steps of 50 mg over several weeks. Usual dose range is 50-200 mg daily.
• Child (6-12 years): Initially 25 mg daily, increased to 50 mg daily after 1 week, further increased if necessary in steps of 50 mg at intervals of at least 1 week (maximum 200 mg daily).

Post-traumatic stress disorder:

• Adult: Initially 25 mg daily, increased after 1 week to 50 mg daily; if response is partial and if drug is tolerated, dose can be increased in steps of 50 mg over several weeks to maximum 200 mg daily.
• Child and adolescent less than 18 years: Not recommended.

Side Effects

Side effects, if occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. The most frequent side effects are drowsiness and light headedness. The other side effects, that may occur include depression, headache, confusion, dry mouth, constipation etc.

Sertraline may cause side effects like upset stomach, diarrhoea, constipation, vomiting, dry mouth, loss of appetite, weight changes, drowsiness, dizziness, headache, pain, burning or tingling in the hands or feet, excitement, sore throat etc.

Toxicity

Alprazolam overdose can present as sleepiness, confusion, poor coordination, slow reflexes, coma, and death. Taking alprazolam with alcohol lowers the threshold for overdose. Patients should have their respiration, pulse, and blood pressure monitored. Patients can be treated by gastric lavage and intravenous fluids.. If hypotension occurs, patients may be treated with vasopressors. In known, or suspected overdoses, patients can be given the benzodiazepine receptor antagonist flumazenil in addition to other methods of management.

Oral LD50 in rats is 331-2171mg/kg.

Alprazolam is a pregnancy category D teratogen meaning there is evidence of risk to the fetus of a mother taking alprazolam but in some cases the benefit may outweigh the risk. Children born to these mothers are also at risk of withdrawal symptoms, flaccidity, and respiratory issues.

Benzodiazepines are expressed in human breast milk and so nursing is generally not recommended in mothers taking alprazolam.

Alprazolam is not associated with carcinogenicity, mutagenicity, or impairment of fertility.

The LD50 of sertraline is >2000 mg/kg in rats according to the FDA label. One other references indicates an oral LD50 of in mice and rats of 419 - 548 mg/kg and 1327 - 1591mg/kg, respectively.

The most common signs and symptoms associated with a non-fatal sertraline overdose are somnolence, vomiting, tachycardia, nausea, dizziness, agitation, and tremor. No cases of fatal overdose with only sertraline have been reported. Most fatal cases are associated with the ingestion of sertraline with other drugs. Consequences of a sertraline overdose may include serotonin syndrome, hypertension, hypotension, syncope, stupor, coma, bradycardia, bundle branch block, QT-prolongation, torsade de pointes, delirium, hallucinations, and pancreatitis.

Precaution

Because Alprazolam may produce psychological and physical dependence, increment of dose or abrupt discontinuation of Alprazolam therapy should not be done without physician's advice. Duration of therapy must be determined by the physicians. Alprazolam should be administered with caution to patients with hepatic or renal disease, chronic pulmonary insufficiency or sleep apnea.

Precaution should be taken in case of liver problems, kidney diseases, seizures, heart problems and any allergies. This drug may cause dizziness or drowsiness. Caution should be taken in activities requiring alertness such as driving or using machinery. Caution is advised while using this product in the elderly because they may be more sensitive to the effects of the drug. Do not take this drug if you have taken monoamine oxidase inhibitor in the last five weeks.

Interaction

Alprazolam produces additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.

Potential effects of co-administration of drugs that are highly bound to plasma proteins- As Sertraline is tightly bound to plasma protein, the administration of Sertraline to a patient taking another drug which is tightly bound to protein, (e.g. warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely adverse effects may result from displacement of protein bound Sertraline by other tightly bound drugs. Sertraline may interact with other drugs such as Cimetidine, CNS active drugs like Diazepam, Hypoglycemic drugs, Atenolol etc.

Volume of Distribution

Volume of distribution following oral administration is 0.8-1.3L/kg. Alprazolam crosses the blood-brain barrier.

Sertraline is widely distributed, and its volume of distribution is estimated to be more than 20L/kg. Post-mortem studies in humans have measured liver tissue concentrations of 3.9–20 mg/kg for sertraline and between 1.4 to 11 mg/kg for its active metabolite, N-desmethyl-sertraline (DMS). Studies have also determined sertraline distributes into the brain, plasma, and serum.

Elimination Route

Oral bioavailability of a standard release tablet of alprazolam is 84-91% with a time to maximum concentration of 1.8 hours. A 1mg oral dose of alprazolam leads to a maximum plasma concentration of 12-22mcg/L. Alprazolam is rapidly absorbed in the gastrointestinal tract.

Data for the area under the curve and the effect of taking alprazolam with food are not readily available.

Following once-daily administration of 50 to 200 mg for two weeks, the mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours after administration, and measured at 20 to 55 μg/L. Steady-state concentrations are reached after 1 week following once-daily administration, and vary greatly depending on the patient. Bioavailability has been estimated to be above 44%. The area under the curve in healthy volunteers after a 100mg dose of sertraline was 456 μg × h/mL in one study.

Effects of food on absorption

The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects given a single dose with and without food. For the tablet, AUC was slightly increased when sertraline was administered with food, the Cmax was 25% greater, and the time to peak plasma concentration was shortened by about 2.5 hours. For the oral concentrate preparation of sertraline, peak concentration was prolonged by approximately 1 hour with the ingestion of food.

Half Life

11.2 hours in healthy patients. The half life is 16.3h in the elderly, 5.8-65.3h in patients with alcoholic liver disease, 9.9-40.4h in obese patients. The half life is 25% higher in Asian patients compared to Caucasians. Other studies have shown the half life to be 9-16h.

The elimination half-life of sertraline is approximately 26 hours. One reference mentions an elimination half-life ranging from 22-36 hours.

Clearance

Oral clearance is 0.90±0.21mL/min/kg but this increases to 2.13±0.54mL/min/kg when given with CYP3A inducers. Other studies have demonstrated a clearance of 0.70-1.5mL/min/kg.

In pharmacokinetic studies, the clearance of a 200mg dose of sertraline in studies of both young and elderly patients ranged between 1.09 ± 0.38 L/h/kg - 1.35 ± 0.67 L/h/kg.

Elimination Route

Alprazolam is mainly eliminated in the urine. A large portion of the dose is eliminated as unmetabolized alprazolam. 2

Since sertraline is extensively metabolized, excretion of unchanged drug in the urine is a minor route of elimination, with 12-14% of unchanged sertraline excreted in the feces.

Pregnancy & Breastfeeding use

Pregnancy: Alprazolam has been categorized in pregnancy category D; that means, it should be avoided in pregnancy.

Lactation: Like other benzodiazepines, Alprazolam is assumed to be excreted in breast milk. Therefore, nursing should not be undertaken by mothers who must use Alprazolam.

Pregnancy: Although animal studies did not provide any evidence of teratogenicity, the safety of Sertraline during human pregnancy has not been established.

Lactation: Sertraline is known to be excreted in breast milk. Its effects on the nursing infant have not yet been established. If treatment with Sertraline is considered necessary, discontinuation of breast-feeding should be considered.

Contraindication

Contraindicated in patients with hypersensitivity to alprazolam or other benzodiazepines. Alprazolam is also contraindicated in patients with myasthenia gravis, acute narrow angle glaucoma, during pregnancy and also in infants.

Sertraline is contraindicated in patients with a known hypersensitivity to Sertraline or any of the excipients of drug.

Special Warning

Use in Children: Safety and efficacy of Alprazolam in patients under the age of 18 years has not been established.

Acute Overdose

Manifestations of Alprazolam over dosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. In such cases of over dosage general supportive measures should be employed along with immediate gastric lavage.

Storage Condition

Alprazolam tablets should be stored in a cool and dry place, protected from light and moisture.

Store at 25° C.

Innovators Monograph

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