Clonapax P

Uses

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

Propranolol is used for:

• essential and renal hypertension
• angina pectoris
• long term prophylaxis after recovery from acyte myocardial infarction
• cardiac dysrhythmia
• prophylaxis of migraine
• essential tremor
• anxiety and anxiety tachycardia
• adjunctive management of thyrotoxicosis and thyrotoxic crisis
• hypertrophic obstructive cardiomyopathy
• phaeochromocytoma (with α-blocker)

Clonapax P is also used to associated treatment for these conditions: 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 SeizuresAkathisia caused by antipsychotic use, Angina Pectoris, Atrial Fibrillation, Cardiovascular Mortality, Gastroesophageal variceal hemorrhage prophylaxis, Hemangiomas, High Blood Pressure (Hypertension), Migraine, Myocardial Infarction, Obstructive Hypertrophic Cardiomyopathy, Performance Anxiety, Pheochromocytomas, Proliferating Infantile Hemangioma, Supraventricular Arrhythmias, Tachyarrhythmia caused by Digitalis intoxication, Tachyarrhythmia caused by catecholamine excess, Thyroid Crisis, Thyrotoxicosis, Tremor caused by lithium, Tremor, Essential, Ventricular Tachycardia (VT)

How Clonapax P works

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 .

Propranolol is a nonselective β-adrenergic receptor antagonist. Blocking of these receptors leads to vasoconstriction, inhibition of angiogenic factors like vascular endothelial growth factor (VEGF) and basic growth factor of fibroblasts (bFGF), induction of apoptosis of endothelial cells, as well as down regulation of the renin-angiotensin-aldosterone system.

Dosage

Clonapax P dosage

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.

Tablet:

Adults:

• Hypertension: A starting dose of 80 mg twice a day may increased at weekly intervals according to response. The usual dose range is 160-320 mg per day. With concurrent diuretic or other antihypertensive drugs a further reduction of blood pressure is obtained.
• Angina, anxiety, migraine and essential tremor: A staring dose of 40 mg two or three times daily may be increased by the same amount at weekly intervals according to patients response. An adequate response in anxiety, migraine and essential tremor is usually seen in the range 80-160 mg/day and an angina in the range 120-240 mg/day.
• Situational and generalized anxiety: A dose of 40 mg daily may provide short term relief of acute situational anxiety. Generalized anxiety require long term therapy, usually responds adequately to 40 mg twice daily which ,which individual cases, may be increased to 40 mgthree times daily. Treatment should be continued according to responses. Patients should reviewed after 6 to 12 months treatment.
• Dysrhythmias, anxiety tachycardia, hypertrophic obstructive cardiomyopathy and thyrotoxicosis: A dosage range of 10-40 mg three or four times a day usually achieves the required response.
• Post myocardial infarction: Treatment should be started between days 5 and after 21 after myocardial infarction, with an initial dose of 40 mg four times a day for 2 or 3 days. In order to improve compliance the total daily doses three after be given as 80 mg twice a day. Phaeochromocytoma (Used only with an alpha receptor blocking drug).
• Pre-operative: 60 mg daily for three days.
• Non-operable malignant cases: 30 mg daily.
• Migraine: Under 12 years: 20 mg two or three times daily.Over 12 years : The adult dose.

Children:

• Sysrhythmias, Phaeochromocytoma, Thyrotoxicisis: Dosage should be individually determined and the following is only a guide 0.25-0.5 mg/kg three or four times daily as required.

Sustained Release Capsule:

Adult:

• Hypertension: The usual initial dose is 80mg Propranolol SR once daily, whether used alone or added to a diuretic. The usual maintenance dosage is 120 to 160 mg once daily.
• Angina pectoris: Starting with 80mg Propranolol SR once daily, dosage should be gradually increased three to seven day intervals until optimum response is obtained.
• Migraine: The initial oral dose is 80 mg Propranolol SR once daily. T he usual effective dose range is 160 to 240 mg once daily. It may be advisable to withdraw the drug gradually over a period of several weeks.
• Hypertrophic subaortic stenosis: 80 mg Propranolol SR once daily

Injection:

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The usual dose is 1 to 3 mg administered under careful monitoring, such as electrocardiography and central venous pressure. The rate of administration should not exceed 1 mg (1 mL) per minute to diminish the possibility of loweringblood pressureand causing cardiac standstill.

Sufficient time should be allowed for the drug to reach the site of action even when a slow circulation is present. If necessary, a second dose may be given after two minutes. Thereafter, additional drug should not be given in less than four hours. Additional propranolol hydrochloride should not be given when the desired alteration in rate or rhythm is achieved.

Transfer to oral therapy as soon as possible.

Side Effects

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.

Propranolol is usually well tolerated. Minor side effects such as cold extremities, nausea, diarrhea, sleep disturbances and lassitude are often transient. There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs.

Toxicity

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 .

Symptoms of overdose include hypotension, hypoglycemic seizure, restlessness, euphoria, insomnia. Patients with asthma may develop bronchospasm. In case of overdose, monitor vital signs, mental status, and blood glucose. Treat hypotension with intravenous fluids, bradycardia with atropine, and isoproterenol and aminophylline for bronchospasm. If patients do not respond to intravenous fluids, follow up with glucagon 50-150µg/kg intravenously, then 1-5mg/hour, followed by catecholamines. Dialysis will not be useful as propranolol is highly protein bound.

Precaution

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.

Beta-adrenoceptor blocking drugs should be avoided in over heart failure. Propranolol modifies the tachycardia of hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin.

Interaction

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

Beta-adrenoceptor blocking drugs interact with clonidine.If beta-adrenoceptor blocking drugs and clonidine are given concurrently, clonidine should be discontinued until several days after withdrawal of beta-adrenoceptor blocking drug. Care should be taken in prescribing a beta-adrenoceptor blocking drugs with class 1 antidysrhythmic agents (disopyramide).Beta-adrenoceptor blocking drugs should be used with caution in combination with verapamil in patients with impaired ventricular function.

Volume of Distribution

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 .

The volume of distribution of propranolol is approximately 4L/kg or 320L.

Elimination Route

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 .

Patients taking doses of 40mg, 80mg, 160mg, and 320mg daily experienced C_max values of 18±15ng/mL, 52±51ng/mL, 121±98ng/mL, and 245±110ng/mL respectively. Propranolol has a T_max of approximately 2 hours, though this can range from 1 to 4 hours in fasting patients. Taking propranolol with food does not increase T_max but does increase bioavailability.

Half Life

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

The elimination half life of propranolol is approximately 8 hours. The plasma half life of propranolol is 3 to 6 hours.

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 .

The clearance of propranolol is 2.7±0.03L/h/kg in infants 90 days. Propranolol clearance increases linearly with hepatic blood flow. Propanolol has a clearance in hypertensive adults of 810mL/min.

Elimination Route

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 .

91% of an oral dose of propranolol is recovered as 12 metabolites in the urine.

Pregnancy & Breastfeeding use

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.

There are no adequate and controlled studies in pregnant women. Propranolol is excreted in human milk. Caution should be exercised when propranolol is administered to a nursing mother.

Contraindication

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.

Propranolol Hydrochloride is contraindicated in patients with known Hypersensitivity to any component of the formulation. If there is a history of bronchial asthma of bronchospasm.

Acute Overdose

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.

The symptoms of over dosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm. Treatment of over dosage include close supervision, treatment in an intensive care ward, he use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock.

Storage Condition

Store at 25°C.

Store in a cool dry place. Protect from light.

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