Norep Plus H

Uses

Citalopram is used for depressive illness and panic disorder. It is also used for substance abuse disorders and alcohol dependence. Citalopram has also been given in variety of anxiety disorders including obsessive-compulsive disorder and social phobia. It is also effective in generalized anxiety disorder, post-traumatic stress disorder, premenstrual syndrome, idiopathic Parkinson's disease and eating disorder.

Clonazepam (Oral) is used for:

Tablet:

• Anxiety disorders (Generalized, Phobic & Panic disorders)

• Insomnia and sleep disturbances

• Labile arterial hypertension

• Peri and Post menopausal anxiety (Anxiety in middle aged women)

• Burning Mouth Syndrome

• Peri and Post menopausal anxiety (Anxiety in middle aged women)

• Postoperative anxiety disorder

• Post traumatic stress disorder

• Anxiety in cancer patient (palliative treatment)

• Tension Headache

• Restless legs syndrome (RLS) or Wittmaack–Ekbom syndrome

• Nocturnal myoclonus

• Tourette's syndrome

• Bipolar affective disorder

• Resistant depression

• Drug-induced dyskinesia

• Choreiform movement

• Fulgurant pain

• Trigeminal neuralgia

• Epilespsy

Injection:

• Epilepsy

• Status epilepticus

• Myoclonic seizure

• Typical and atypical absences (Lennox-Gastaut syndrome)

• Infantile spasm

• Tonic-clonic seizure

• Partial seizure

• Absence seizure

• Focal seizure

Norep Plus H is also used to associated treatment for these conditions: Anorexia Nervosa (AN), Bulimia Nervosa, Depression, Diabetic Neuropathies, Major Depressive Disorder (MDD), Obsessive Compulsive Disorder (OCD), Panic Disorder, Post Traumatic Stress Disorder (PTSD), Premature Ejaculation, Premenstrual Dysphoric Disorder, Social Anxiety Disorder (SAD)Akinetic seizures, Burning Mouth Syndrome, Gilles de la Tourette's Syndrome, Lennox-Gastaut Syndrome (LGS), Mixed manic depressive episode, Panic Disorder, Rapid Eye Movement Sleep Disorder, Restless Legs Syndrome (RLS), Tardive Dyskinesia (TD), Tremor, Essential, Acute Manic episode, Myoclonic seizures, Refractory absence Seizures

How Norep Plus H works

The mechanism of action of citalopram results from its inhibition of CNS neuronal reuptake of serotonin (5-HT) . The molecular target for citalopram is the serotonin transporter (solute carrier family 6 member 4, SLC6A4), inhibiting its serotonin reuptake in the synaptic cleft .

Citalopram binds with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs . This drug has no or neglible affinity for 5-HT1A, 5-HT2A, dopamine D1 and D2, α1-, α2-, and_ β­ adrenergic, _histamine H1, gamma-aminobutyric acid (GABA), muscarinic, cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic, and adrenergic receptors is thought to be associated with several anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs .

Gamma-Aminobutyric acid (GABA) is considered the principal inhibitory neurotransmitter in the human body . When GABA binds to GABA(a) receptors found in neuron synapses, chloride ions are conducted across neuron cell membranes via an ion channel in the receptors . With enough chloride ions conducted, the local, associated neuron membrane potentials are hyperpolarized - making it more difficult or less likely for action potentials to fire, ultimately resulting in less excitation of the neurons .

Subsequently, benzodiazepines like clonazepam can bind to benzodiazepine receptors that are components of various varieties of GABA(a) receptors . This binding acts to enhance the effects of GABA by increasing GABA affinity for the GABA(a) receptor, which ultimately enhances GABA ligand binding at the receptors . This enhanced ligand binding of the inhibitory neurotransmitter GABA to the receptors increases the aforementioned chloride ion conduction (perhaps reportedly via an increase in the frequency of the chloride channel opening), resulting in a hyperpolarized cell membrane that prevents further excitation of the associated neuron cells . Combined with the notion that such benzodiazepine receptor associated GABA(a) receptors exist both peripherally and in the CNS, this activity consequently facilitates various effects like sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and anxiolytic action .

In particular, when out of the ordinary rapid and repetitive electrical signals are released in the CNS, it is proposed that the brain can become over-stimulated and ordinary functions are disrupted - resulting in seizure activity . By enhancing the neuro-inhibitory activity of GABA, it is believed that clonazepam can facilitate in decreasing any excessive electrical nerve activity in the CNS that might be contributing to seizures . Concurrently, it is also believed that clonazepam's actions in enhancing GABA effects may inhibit neuronal activity proposed to occur in amygdala-centered fear circuits - therefore assisting in the management of anxiety or panic .

Dosage

Norep Plus H dosage

Depressive illness 20 mg daily as a single dose in the morning or evening; increased ifnecessary to maximum 60 mg daily (Elderly maximum 40 mgdaily).Panic disorder Initially 10 mg daily, increased to 20 mg after 7 days; usual dose 20-30 mg daily; maximum 60 mg daily (Elderly maximum 40 mgdaily).

Tablet:

Infants and children

Initial dose: 0.01 - 0.03 mg/kg/day. Up to 1 year: 0.25 mg daily in divided dose, not to exceed 0.05 mg/kg/days increase gradually to 0.5 - 1 mg.

Increment dose: not more than 0.25 - 0.5 mg 1 - 5 years: 0.25 mg daily in divided dose, at intervals of 3 days increase to 1 - 3 mg.

Maintenance dose: 0.1 - 0.2 mg/kg/day. 5 - 12 years: 0.5 mg daily in divided dose,

Dosing interval: b.i.d. / t.i.d. increase to 3 - 6 mg.

Adults and elderly

Initial dose: 1 mg daily in divided dose (Elderly 0.5 mg), not to exceed 1.5 mg/day

Increment dose: 0.5 - 1 mg at intervals of 3 days

Maintenance dose: 4 - 8 mg/day

Maximum dose: 20 mg/day should be administered with caution

Dosing interval: b.i.d. / t.i.d.

Initial dose should be low and increased gradually to a maintenance dose that controls seizure without toxic effects. During discontinuation, the dose should be tapered.

Injection:

Infants and children: half of a vial (0.5 mg) by slow IV injection or by IV infusion. Adults: 1 vial (1 mg) by slow IV injection or by IV infusion. This dose can be repeated as required (1 - 4 mg are usually sufficient to reverse the status). In adults, the rate of injection must not exceed 0.25 - 0.5 mg per minute (0.5 – 1.0 mL of the prepared solution) and a total dose of 10 mg should not be exceeded.

Slow intravenous injection: The contents of the vial must be diluted with 1 mL of water for injection prior to administration so as to avoid local irritation of the veins. The injection solution should be prepared immediately before use. IV injection should be administered slowly with continuous monitoring of EEG, respiration and blood pressure.

Intravenous infusion: Clonazepam (the vial) can be diluted for infusion in a ratio of 1 vial (1 mg) to at least 85 mL diluting media. The diluting media can be any of the following: sodium chloride 0.9%; sodium chloride 0.45% + glucose 2.5%; glucose 5% or glucose 10%. These mixtures are stable for 24 hours at room temperature. Infusion bags other than PVC should be used for infusing Clonazepam. If PVC infusion bags are used then the mixture should be infused immediately or within 4 hours. The infusion time should not exceed 8 hours. Do not prepare Clonazepam infusions using sodium bicarbonate solution, as precipitation of the solution may occur.

Intramuscular injection: The IM route should be used only in exceptional cases or if IV administration is not feasible.

Side Effects

SSRIs are less sedating and have fewer antimuscarinic and cardiotoxic effects than tricyclic antidepressants. However, side-effects may be seen, includes gastro-intestinal effects (nausea, vomiting, dyspepsia, abdominal pain, diarrhoea, constipation), anorexia with weight loss, palpitations, tachycardia, postural hypotension, cough, confusion, impaired concentration, amnesia, urinary retention, sweating, movement disorders, urticaria, anaphylaxis, arthralgia, myalgia and photosensitivity.

Tablet:

The most frequently occurring side effects of clonazepam are referable to CNS depression, drowsiness, fatigue, dizziness, muscle hypotonia, co-ordination disturbance, hypersalivation in infants, paradoxical aggression, irritability and mental change.

Injection:

Some side effects, like: fatigue, muscle weakness, dizziness, somnolence, light-headedness, ataxia, restlessness, hypersalivation in infants, paradoxical aggression, reduced co-ordination may occur with Clonazepam therapy but these effects are transient and generally disappears in the course of the treatment. Respiratory depression may occur in patients with pre-existing airways obstruction, or brain damage, or if other medications which depress respiration have been given. As a rule, this effect can be avoided by careful adjustment of the dose to individual requirements.

Toxicity

Oral (Human) LD: 56 mg/kg Intraperitoneal (Mouse) LD50: 179 mg/kg

Acute toxicity

Symptoms of toxicity include dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. Rarely, symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and extremely rare cases of cardiac torsade de pointes) may occur. Acute renal failure has been a rare occurrence .

In cases of overdose, establish and maintain the airway to ensure adequate ventilation and oxygen delivery. Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are advised, in addition to supportive care. With the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit .

Pregnancy

This drug is categorized as pregnancy category C. In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, which includes teratogenic effects when given at doses higher than human therapeutic doses. There are no sufficient and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only in cases where the potential benefit justifies the possible risk to the fetus .

Pregnancy-Nonteratogenic Effects

Neonates exposed to celexa and other SSRIs or SNRIs, late in the third trimester, have undergone complications requiring prolonged hospitalization, respiratory support, and parenteral feeding. Complications such as these can arise immediately upon delivery .

Nursing Mothers

Citalopram is excreted in human breast milk. There have been two reports of infants demonstrating high levels of somnolence, reduced feeding, and weight loss associated with breastfeeding from a mother taking citalopram. In one specific case, the infant was reported to recover completely after the discontinuation of citalopram. In the second case, no follow-up information was available for assessment. The decision whether to continue or discontinue either nursing or celexa should consider the risks of citalopram exposure for the infant versus the benefits of celexa treatment for the mother .

Benzodiazepines like clonazepam commonly cause drowsiness, ataxia, dysarthria, and nystagmus. Overdose with clonazepam is generally not life-threatening if the drug is taken alone, but may lead to areflexia, apnea, hypotension, cardiorespiratory depression, and coma. Coma, if it does occur, usually lasts a few hours but it can become more protracted and cyclical, especially in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious when compounded in patients with respiratory disease.

An increased risk of congenital malformations associated with the use of benzodiazepine drugs like clonazepam has been suggested in several studies . There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy . There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy . In addition, children born to mothers receiving benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period . In general, it is best for patients who are of childbearing potential and also use benzodiazepines like clonazepam to discuss such matters with their health care professionals as careful consideration must be undertaken regarding the intersection of the risks of untreated seizure potential in the patient and any possible toxicity to the fetus .

Although the active ingredient of clonazepam has been found to pass into the maternal milk in small amounts only, mothers receiving clonazepam should not breast-feed their infants .

Since the possibility that adverse effects on the physical or mental development of the child could become apparent only after a number of years, the risk-benefit consideration of the long-term use of clonazepam in pediatric patients younger than five years of age is important .

The pharmacological effects of benzodiazepines like clonazepam appear to be greater in elderly patients than in younger patients even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug-receptor interactions, post-receptor mechanisms, and organ function . In general elderly patients should be started on the lowest possible dose of clonazepam and observed closely . There is an increased risk for falls and fractures among elderly and debilitated benzodiazepine users . The risk is increased in those taking concomitant sedatives, including substances like benzodiazepines, alcoholic beverages, and so on .

Some oral LD50 values documented are >4000 mg/kg for the mouse model, >4000 mg/kg for the adult rat model, and >2000 mg/kg for the rabbit model .

Precaution

Caution should be taken in patients with epilepsy, concurrent electroconvulsive therapy, history of mania, cardiac disease, diabetes mellitus, angle-closure glaucoma, history of bleeding disorders, hepatic and renal impairment. Abrupt withdrawal of Citalopram should be avoided.

Tablet:

When used in patients in whom several different types of seizure disorders coexist, clonazepam may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal). This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and clonazepam may produce absence status. Periodic blood counts and liver function tests are advisable during long term therapy with clonazepam.

The abrupt withdrawal of clonazepam, particularly in those patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore when discontinuing clonazepam, gradual withdrawal is essential.

Clonazepam may produce an increase in salivation. This should be considered before giving the drug to patients who have difficulty handling secretions. Because of this and the possibility of respiratory depression, clonazepam should be used with caution in patients with chronic respiratory diseases.

Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of clonazepam is important in pediatric patients.

Injection:

The concomitant use of Clonazepam with alcohol and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Clonazepam, such as: severe sedation, respiratory and cardiac depression. In some cases, dose adjustment of other medications is necessary. Clonazepam may produce an increase in salivation. This should be considered before giving the drug to patients who have difficulty handling secretions. Clonazepam is adviced to use with caution in patients with chronic respiratory diseases. Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of clonazepam is important in pediatric patients.

Interaction

Ketoconazole, Itraconazole or Macrolide antibiotics and Citalopram co-administration decreases the metabolism of Citalopram. Omeprazole and Citalopram co-administration might decrease the clearance of Citalopram.

Interactions have been reported between some benzodiazepines and other anticonvulsants, with changes in the serum concentration of the benzodiazepine or anticonvulsant.

Volume of Distribution

12 L/kg

Citalopram is highly lipophilic and likely widely distributed throughout the body, including the blood-brain-barrier. However, its metabolite, demethylcitalopram does not penetrate the blood-brain-barrier well .

Clonazepam distributes very rapidly to various organs and body tissues with preferential uptake by brain structures . The apparent volume of distribution has been documented as approximately 3 L/kg .

Elimination Route

Rapidly and well absorbed from the GI tract. Peak plasma concentrations occur within 4 hours of a single orally administered dose. Bioavailability is 80% following oral administration. Food does not affect absorption .

Clonazepam is rapidly and almost entirely absorbed after oral administration as tablets . Peak plasma concentrations of clonazepam administered by the oral route are reached within 1-4 hours and the associated absorption half-life is about 25 minutes . The absolute bioavailability is approximately 90% - but with substantially large differences between individuals .

Half Life

About 35 hours .

The mean elimination half-life determined for clonazepam is independent of the dose given and has been documented as being about 30-40 hours .

Clearance

The systemic clearance of citalopram is 330 mL/min, with approximately 20% renal clearance .

The documented clearance for clonazepam is approximately 55 ml/min regardless of gender . Nevertheless, clearance values normalized by weight decline with increasing body weight .

Elimination Route

12-23% of an oral dose of citalopram is found unchanged in the urine, while 10% of the dose is found in the faeces .

Approximately 50-70% of a clonazepam dose is excreted in the urine and 10-30% is excreted in the feces as metabolites . The excretion of unchanged clonazepam in the urine is typically less than 2% of the administered dose . Metabolites of clonazepam are present in urine as both free and conjugated (glucuronide and sulfate) compounds .

Pregnancy & Breastfeeding use

PregnancyThere are no adequate and well-controlled studies in pregnant women; therefore, Citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

LactationCitalopram is excreted in human breast milk. So, the decision whether to continue or discontinue either nursing or Citalopram therapy should take into account the risks of Citalopram exposure for the infants and the benefits of Citalopram treatment for the mother.

The use of clonazepam during pregnancy or lactation should be avoided. Clonazepam is excreted into the breast milk and should therefore be avoided in breast-feeding mothers.

Contraindication

Citalopram should not be used if the patient enters a manic phase. Concomitant use in patients taking MAO inhibitor is contraindicated. Citalopram is contraindicated in patients with a hypersensitivity to this drug or any of its ingredients.

Clonazepam should not be used in patients with a history of sensitivity to benzodiazepine, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow angle glaucoma.

Acute Overdose

It is a very safe drug. There were no reports of fatal Citalopram overdose in clinical trials involving overdoses of up to 2000 mg.

Symptoms: Dizziness, sweating, nausea, vomiting, tremor, somnolence and sinus tachycardia. Rarely, amnesia, confusion, coma, seizures, hyperventilation, cyanosis, rhabdomyolysis and ECG changes (e.g. QT prolongation, sinus bradycardia, ventricular arrhythmias, nodal rhythm, torsade de pointes and left bundle branch block).

Management: Symptomatic and supportive treatment. Maintain and ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Frequently monitor cardiac function and vital signs.

Tablet:

Symptoms of clonazepam overdosage, like those produced by other CNS depressants, include somnolence, confusion, coma and diminished reflexes.

Injection:

Symptoms of Clonazepam overdosage, like those produced by other CNS depressants, include: somnolence, confusion, coma and diminished reflexes.

Storage Condition

Store at 25° C.

Store at 25°C.

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