Find Medicines

Epirubicin Injection is an anthracycline topoisomerase II inhibitor indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer

Cytotoxic Chemotherapy

Epirubicin, an anthracycline with cytotoxic properties. It inhibits DNA and RNA synthesis by steric obstruction after intercalating between DNA base pairs that triggers DNA cleavage by by topoisomerase II. It also inhibits DNA helicase and generates cytotoxic free radicals.

Acute leukaemias; Lymphoma; Multiple myeloma; Solid tumours:

• As a single agent: 60-90 mg/m² 3-4 wkly.
• Max (total cumulative dose): 0.9-1 g/m².
• Palliative care: 12.5-25 mg/m² once wkly.

Adjuvant treatment in axillary-node positive breast cancer: Recommended starting doses: 100-120 mg/m² as a single dose on day 1 or as 2 divided doses on days 1 and 8 of each 28-day cycle. Repeat for 6 cycles.

Intravesical Local treatment of bladder carcinoma: As 0.1% soln: 50 mg/wk for 8 wk; reduce dose if chemical cystitis develops.

For carcinoma in-situ: 80 mg in 50 mL wkly.

For prevention of recurrence in patients who have undergone transurethral resection: 50 mg/wk for 4 wk, followed by 50 mg/mth for 11 mth; retain soln in the bladder for 1 hr during each administration.

In early breast cancer, acute adverse events occurring in ≥10% of patients are leucopenia, neutropenia, anemia, thrombocytopenia, amenhorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local toxicity and rash/itch.

Long term adverse events occurring at a frequency of 1-2% are asymptomatic drops in LVEF and CHF and secondary leukemia.

Cardiac impairment, severe or recent Ml; previous full cumulative doses of anthracyclines. Hypersensitivity; severe hepatic dysfunction. Not for intravesical use where invasive tumours have penetrated the bladder wall; urinary infections, bladder inflammation or catheterisation problems. Pregnancy, lactation.

Previous extensive radiotherapy, bone infiltration by tumour, severe renal and hepatic dysfunction. May cause tumor lysis syndrome or radiation recall. Elderly women >70 yr. CV disease, hypertensive cardiomyopathy; monitor hematological and cardiac function regularly. Extravasation during IV admin may result in severe local tissue necrosis. Do not give via IM/SC routes as extravasation can lead to severe local necrosis

Paclitaxel and other anthracyclines. Cimetidine, heparin. Antineoplastic drugs, cardiotoxic drugs, radiation, hepatoactive drugs.

Discontinue nursing prior to taking Epirubicin. Not known if excreted in breast milk

Adjunct anti-epileptic drugs, Benzodiazepine hypnotics

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

There are also animal data showing an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.

Oral:

• Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

• The initial dose for adults with panic disorder is 0.25 mg given in two divided dose. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
• Pediatric Patients: In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

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.

The most frequently occurring side effects of Clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Abnormal eye movements, aphonia, coma, tremor, vertigo, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis & palpitations may also occur.

It should not be used in patients with a history of hypersensitivity to benzodiazepines, 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.

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. 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.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of Clonazepam on the metabolism of other drugs has not been investigated.

Pregnancy: From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines.

Nursing Mothers: Although the active ingredient of Clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Clonazepam, breastfeeding should be discontinued.

Pediatric Use: In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways. 

Geriatric Use: Benzodiazepine pharmacologic effects 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.

Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.

Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Clonazepam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment: Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

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.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Adjunct anti-epileptic drugs, Benzodiazepine hypnotics

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

There are also animal data showing an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.

Oral:

• Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

• The initial dose for adults with panic disorder is 0.25 mg given in two divided dose. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
• Pediatric Patients: In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

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.

The most frequently occurring side effects of Clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Abnormal eye movements, aphonia, coma, tremor, vertigo, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis & palpitations may also occur.

It should not be used in patients with a history of hypersensitivity to benzodiazepines, 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.

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. 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.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of Clonazepam on the metabolism of other drugs has not been investigated.

Pregnancy: From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines.

Nursing Mothers: Although the active ingredient of Clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Clonazepam, breastfeeding should be discontinued.

Pediatric Use: In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways. 

Geriatric Use: Benzodiazepine pharmacologic effects 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.

Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.

Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Clonazepam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment: Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

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.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Adjunct anti-epileptic drugs, Benzodiazepine hypnotics

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

There are also animal data showing an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.

Oral:

• Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

• The initial dose for adults with panic disorder is 0.25 mg given in two divided dose. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
• Pediatric Patients: In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

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.

The most frequently occurring side effects of Clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Abnormal eye movements, aphonia, coma, tremor, vertigo, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis & palpitations may also occur.

It should not be used in patients with a history of hypersensitivity to benzodiazepines, 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.

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. 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.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of Clonazepam on the metabolism of other drugs has not been investigated.

Pregnancy: From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines.

Nursing Mothers: Although the active ingredient of Clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Clonazepam, breastfeeding should be discontinued.

Pediatric Use: In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways. 

Geriatric Use: Benzodiazepine pharmacologic effects 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.

Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.

Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Clonazepam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment: Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

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.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Brivaracetam is indicated for the treatment of partial-onset seizures in patients 4 years of age and older. As the safety of Brivaracetam injection in pediatric patients has not been established, Brivaracetam injection is indicated for the treatment of partial-onset seizures only in adult patients (16 years of age and older).

Adjunct anti-epileptic drugs

The precise mechanism by which Brivaracetam exerts its anticonvulsant activity is not known. Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.

Brivaracetam binds SV2A with high affinity. SV2A is known to play a role in epileptogenesis through modulation of synaptic GABA release. It is thought that brivaracetam exerts its anti-epileptogenic effects through its binding to SV2A. Brivaracetam is also known to inhibit Na⁺ channels which may also contribute to its anti-epileptogenic action

Adults (16 Years and older): The recommended starting dosage for monotherapy or adjunctive therapy is 50 mg twice daily (100 mg per day).

Based on individual patient tolerability and therapeutic response, the dosage may be adjusted down to 25 mg twice daily (50 mg per day) or up to 100 mg twice daily (200 mg per day).

Pediatric Patients (4 Years to less than 16 Years): The recommended dosage is based on body weight and is administered orally twice daily

Injection: for intravenous and adult use only when oral administration is temporarily not feasible; dosing is the same as oral regimen.

Brivaracetam injection should be administered intravenously over 2 to 15 minutes. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Product with particulate matter or discoloration should not be used. Brivaracetam injection is for single dose only.

Most common adverse reactions (at least 5% for Brivaracetam and at least 2% more frequently than placebo) are somnolence/sedation, dizziness, fatigue, and nausea or vomiting.

Hypersensitivity to brivaracetam or any of the inactive ingredients in Brivaracetam

Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and ideation.

Neurological Adverse Reactions: Monitor for somnolence and fatigue, and advise patients not to drive or operate machinery until they have gained sufficient experience on Brivaracetam.

Psychiatric Adverse Reactions: Behavioral reactions including psychotic symptoms, irritability, depression, aggressive behavior, and anxiety; monitor patients for symptoms.

Hypersensitivity: Bronchospasm and Angioedema: Advise patients to seek immediate medical care. Discontinue and do not restart Brivaracetam if hypersensitivity occurs. 

Withdrawal of Antiepileptic Drugs: Brivaracetam should be gradually withdrawn.

Rifampin: Because of decreased concentrations, increasing Brivaracetam dosage in patients on concomitant rifampin is recommended.

Carbamazepine: Because of increased exposure to carbamazepine metabolite, if tolerability issues arise, consider reducing carbamazepine dosage in patients on concomitant Brivaracetam.

Phenytoin: Because phenytoin concentrations can increase, phenytoin levels should be monitored in patients on concomitant Brivaracetam.

Levetiracetam: Brivaracetam had no added therapeutic benefit when co-administered with levetiracetam.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as Brivaracetam, during pregnancy. No data are available regarding the presence of brivaracetam in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Studies in lactating rats have shown excretion of brivaracetam or metabolites in milk

Hepatic Impairment: Dose adjustment is recommended for all stages of hepatic impairment.

Renal Impairment: Dose adjustments are not required for patients with impaired renal function.

Store at 25°C; excursions permitted between 15°C to 30°C

Ephedrine is indicated to reverse hypotension induced by spinal or epidural anaesthesia. It is of little value in hypotensive crisis due to shock, circulatory collapse, or haemorrhage.

Other adrenoceptor stimulants, Vasoconstrictor/Venotonic

Ephedrine is a stimulant drug, belonging to a group of medicines known as sympathomimetics. Specifically it is both an alpha and beta adrenergic agonist. In addition, Ephedrine enhances the release of norepinephrine, a strong endogenous alpha agonist. The action of this compound is notably similar to that of the body's primary adrenergic hormone epinephrine (adrenaline), which also exhibits action toward both alpha and beta receptors. When administered, Ephedrine will notably increase the activity of the central nervous system, as well as have a stimulatory effect on other target cells.

To reverse hypotension induced by spinal or epidural anaesthesia 3 to 6 mg (or at most 9 mg) Ephedrine Hydrochloride is given by slow intravenous injection and repeated every 3 to 4 minutes as required; the maximum total dose is 30 mg. Ephedrine has also been given by intramuscular or subcutaneous injection.

Adverse effects reported are nausea, vomiting, anorexia; tachycardia (sometimes bradycardia), arrhythmias, anginal pain, vasoconstriction with hypertension, vasodilation with hypotension, dizziness and flushing; dyspnoea; headache, anxiety, restlessness, confusion, psychoses, insomnia, tremor; difficulty in micturition, urine retention; sweating, hypersalivation; changes in blood-glucose concentration; very rarely angle-closure glaucoma.

The use of Ephedrine is contraindicated in the presence of coronary thrombosis. It should be used with caution in patients with organic heart disease, cardiac decompensation, hyperthyroidism, hypertension, and angina pectoris, and in patients receiving digitalis.

Ephedrine should be given with care to patients with hyperthyroidism, diabetes mellitus, ischemic heart disease, hypertension, renal impairment, or angle-close glaucoma. In patients with prostatic enlargement, Ephedrine may increase difficulty with micturition. Use in pregnancy and lactation: Increased fetal heart rate reported with parenteral Ephedrine. Irritability and disturbed sleep have been reported in breast-fed infants.

Administration of Ephedrine may cause a hypertensive crisis in patients receiving an Monoamine Oxidase Inhibitor (including an Reversible Inhibitor of Monoamine Oxidase type A). Ephedrine should be avoided or used with care in patients undergoing anaesthesia with cyclopropane, halothane, or other volatile anaesthetics. An increased risk of arrhythmias may occur if given to patients receiving cardiac glycosides, quinidine, or tricyclic antidepressants, and there is an increased risk of vasoconstrictor or pressor effects in patients receiving ergot alkaloids or oxytocin

Pregnancy: Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Lactation: Ephedrine Hydrochloride is distributed into breast milk, and therefore Ephedrine Hydrochloride Injection is not recommended for use during lactation because of the risk of adverse effects in the infant.

When given in sufficiently large doses Ephedrine gives rise in most patients to certain minor reactions, such as giddiness, headache, nausea, vomiting, sweating, palpitations, difficulty in micturition, tremors, anxiety, restlessness and insomnia; some patients may exhibit these symptoms even with the usual therapeutic dosage.

Store in a cool, dry place, protected from light. Keep all medicines out of reach of children.

Carbamazepine is indicated for-

• partial and secondary generalized tonic-clonic seizures
• Primary generalized tonic-clonic seizures
• Trigeminal neuralgia
• Prophylaxis of bipolar disorder

Primary anti-epileptic drugs

Carbamazepine depresses activity in the nucleus ventralis of the thalamus, reduces synaptic propagation of excitatory impulses or decreases summation of temporal stimulation leading to neural discharge by limiting influx of Na ions across cell membrane or other unknown mechanisms. It stimulates the release of antidiuretic hormone (ADH) and potentiates its action in promoting reabsorption of water.

Epilepsy:

• Adults and children over 12 years of age- Initial: Either 200 mg b.i.d. for tablets and controlled release tablets, or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d or a t.i.d. or q.i.d. regimen of the either formulations until the optimal response is obtained.
• Children 12-15 years of age- Dosage generally should not exceed 1000 mg daily, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances. Maintenance: usually 800-1200 mg daily.
• Children 6-12 years of age- Initial: Either 100 mg b.i.d. for tablets or controlled release tablets, or 1/2 teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. or a t.i.d.or q.i.d. regimen of the either formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance:usually 400-800 mg daily.
• Children under 6 years of age- Initial: 10-20 mg/kg/day b.i.d.or t.i.d. as tablets, or q.i.d. as suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of Carbamazepine for use at doses above 35 mg/kg/24 hours can be made.

Combination therapy: Carbamazepine may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased.

Trigeminal Neuralgia: Initial: On the first day,either 100 mg b.i.d. for tablets or controlled release tablets, or 1/2 teaspoon q.i.d. for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or controlled release tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to achieve freedom from pain. A total dose of 1200 mg daily shouldn't be exceeded. Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug. The tablets or syrup can be taken without regards to meal.

The common side effects are dizziness, drowsiness, ataxia, dry mouth, abdominal pain, nausea, vomiting, anorexia, leucopenia, proteinuria, bradycardia, heart failure and hypotension. Erythematous skin rash, aplastic anemia may also be observed.

The most severe adverse reactions have been observed in the hemopoietic system, the skin and the cardiovascular system.The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. This medicine may cause increased sensitivity to the sun. Exposure to the sun, sunlamps, or tanning booths should be avoided if the increased sensitivity is seen. A sunscreen or protective clothing may be helpful at outside for a prolonged period.

This medicine should not be used if anybody is allergic to one or any of its ingredients. It can not be used also in the following conditions:

• Problems with the electrical message pathways in the heart (atrioventricular block)
• History of decreased blood cell production by the bone marrow (bone marrow depression)
• Hereditary blood disorders called porphyrias
• Allergy to tricyclic antidepressants
• People who have taken a monoamine-oxidase inhibitor antidepressant (MAOI) in the last 14 days

This medicine may cause dizziness and drowsiness.Special care should be taken while performing potentially hazardous activities, such as driving or operating machinery.

This medicine may cause skin reactions. If any rash,skin peeling, itching, or other unexplained skin reaction is seen while taking this medicine the concerned doctor should be informed immediately.

This medicine may rarely cause liver problems.For this reason, consultation with doctor is needed if unexplained itching, yellowing of the skin or eyes, unusually dark urine, nausea and vomiting, abdominal pains, and loss of appetite or flu-like symptoms.

Carbamazepine decreases the blood levels of hormonal contraceptives containing estrogen and/or progesterone, which may make the contraceptive ineffective or result in breakthrough bleeding.

Women taking this medicine who require contraception should be prescribed a contraceptive containing at least 50 micrograms of oestrogen,or use non-hormonal methods of contraception, such as condoms.

Taking this medicine should not be stopped suddenly unless the doctor tells. Otherwise, as suddenly stopping treatment is likely to make the symptoms return.If this medicine is stopped, it should normally be done gradually, under the supervision of a specialist.

Caution should be taken in-

• Mixed seizures including absence seizures
• Elderly people
• History of heart disease
• History of kidney disease
• History of liver disease
• History of psychotic illness
• Raised pressure in the eye (intraocular pressure), eg.glaucoma
• History of blood disorders that were caused by any other medication
• History of previous Carbamazepine therapy that was interrupted due to side effects or allergy

Galactorrhoea has been reported in few women on oral contraceptives within the first two months of Carbamazepine treatment Hepatic enzyme inducers such as Carbamazepine and Phenytoin may interact with Carbamazepine by increasing its metabolism. So an increase in dosage of Carbamazepine may be required.

Pregnancy category D. Carbamazepine and its epoxide metabolite are transferred to breast milk. Because of the potential serious side effects, decision should me made whether to discontinue nursing or discontinue the drug.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Carbamazepine is indicated for-

• partial and secondary generalized tonic-clonic seizures
• Primary generalized tonic-clonic seizures
• Trigeminal neuralgia
• Prophylaxis of bipolar disorder

Primary anti-epileptic drugs

Carbamazepine depresses activity in the nucleus ventralis of the thalamus, reduces synaptic propagation of excitatory impulses or decreases summation of temporal stimulation leading to neural discharge by limiting influx of Na ions across cell membrane or other unknown mechanisms. It stimulates the release of antidiuretic hormone (ADH) and potentiates its action in promoting reabsorption of water.

Epilepsy:

• Adults and children over 12 years of age- Initial: Either 200 mg b.i.d. for tablets and controlled release tablets, or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d or a t.i.d. or q.i.d. regimen of the either formulations until the optimal response is obtained.
• Children 12-15 years of age- Dosage generally should not exceed 1000 mg daily, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances. Maintenance: usually 800-1200 mg daily.
• Children 6-12 years of age- Initial: Either 100 mg b.i.d. for tablets or controlled release tablets, or 1/2 teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. or a t.i.d.or q.i.d. regimen of the either formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance:usually 400-800 mg daily.
• Children under 6 years of age- Initial: 10-20 mg/kg/day b.i.d.or t.i.d. as tablets, or q.i.d. as suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of Carbamazepine for use at doses above 35 mg/kg/24 hours can be made.

Combination therapy: Carbamazepine may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased.

Trigeminal Neuralgia: Initial: On the first day,either 100 mg b.i.d. for tablets or controlled release tablets, or 1/2 teaspoon q.i.d. for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or controlled release tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to achieve freedom from pain. A total dose of 1200 mg daily shouldn't be exceeded. Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug. The tablets or syrup can be taken without regards to meal.

The common side effects are dizziness, drowsiness, ataxia, dry mouth, abdominal pain, nausea, vomiting, anorexia, leucopenia, proteinuria, bradycardia, heart failure and hypotension. Erythematous skin rash, aplastic anemia may also be observed.

The most severe adverse reactions have been observed in the hemopoietic system, the skin and the cardiovascular system.The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. This medicine may cause increased sensitivity to the sun. Exposure to the sun, sunlamps, or tanning booths should be avoided if the increased sensitivity is seen. A sunscreen or protective clothing may be helpful at outside for a prolonged period.

This medicine should not be used if anybody is allergic to one or any of its ingredients. It can not be used also in the following conditions:

• Problems with the electrical message pathways in the heart (atrioventricular block)
• History of decreased blood cell production by the bone marrow (bone marrow depression)
• Hereditary blood disorders called porphyrias
• Allergy to tricyclic antidepressants
• People who have taken a monoamine-oxidase inhibitor antidepressant (MAOI) in the last 14 days

This medicine may cause dizziness and drowsiness.Special care should be taken while performing potentially hazardous activities, such as driving or operating machinery.

This medicine may cause skin reactions. If any rash,skin peeling, itching, or other unexplained skin reaction is seen while taking this medicine the concerned doctor should be informed immediately.

This medicine may rarely cause liver problems.For this reason, consultation with doctor is needed if unexplained itching, yellowing of the skin or eyes, unusually dark urine, nausea and vomiting, abdominal pains, and loss of appetite or flu-like symptoms.

Carbamazepine decreases the blood levels of hormonal contraceptives containing estrogen and/or progesterone, which may make the contraceptive ineffective or result in breakthrough bleeding.

Women taking this medicine who require contraception should be prescribed a contraceptive containing at least 50 micrograms of oestrogen,or use non-hormonal methods of contraception, such as condoms.

Taking this medicine should not be stopped suddenly unless the doctor tells. Otherwise, as suddenly stopping treatment is likely to make the symptoms return.If this medicine is stopped, it should normally be done gradually, under the supervision of a specialist.

Caution should be taken in-

• Mixed seizures including absence seizures
• Elderly people
• History of heart disease
• History of kidney disease
• History of liver disease
• History of psychotic illness
• Raised pressure in the eye (intraocular pressure), eg.glaucoma
• History of blood disorders that were caused by any other medication
• History of previous Carbamazepine therapy that was interrupted due to side effects or allergy

Galactorrhoea has been reported in few women on oral contraceptives within the first two months of Carbamazepine treatment Hepatic enzyme inducers such as Carbamazepine and Phenytoin may interact with Carbamazepine by increasing its metabolism. So an increase in dosage of Carbamazepine may be required.

Pregnancy category D. Carbamazepine and its epoxide metabolite are transferred to breast milk. Because of the potential serious side effects, decision should me made whether to discontinue nursing or discontinue the drug.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Primary anti-epileptic drugs

Sodium Valproate, the active ingredient of this preparation is endowed with anti-epileptic activity against a variety of seizures. The mechanism by which Sodium Valproate exerts its anti-epileptic effects has not been established. However, it has been suggested that its activity is related to increase brain levels of gamma-aminobutyric acid (GABA).

Sodium Valproate tablets may be given once or twice daily. Sodium Valproate syrup should be given in divided doses.

Epilepsy-

• Adults: Initially 600 mg daily given in 2 divided doses, preferably after food, increasing by 200 mg/day at 3-day intervals to a maximum of 2.5 g daily in divided doses until control of seizure is achieved. Usual maintenance dose is 1-2 g daily (20-30 mg/kg daily)
• Children (up to 20 kg): Initially 20 mg/kg daily in divided doses, may be increased provided plasma concentrations monitored (above 40 mg/kg daily also monitor clinical chemistry and hematological parameters).
• Children (over 20 kg): Initially 400 mg daily in divided doses increased until control (usually in the range of 20-30 mg/kg daily) Maximum 35 mg/kg daily.

Febrile convulsion: 20-30 mg/kg/day in 3 divided doses.

Bipolar disorder: Initially 20-30 mg/kg/day in 2-3 divided doses; adjust dosage in 3-5 days. Maintenance dosage is 1000-2000 mg/day.

Prophylaxis of migraine: 300 mg twice daily, although some may require 1000 mg daily.

The most common side effects are anorexia, nausea and vomiting. However, these side effects are minimized with the use of enteric coated tablets. Effects on the CNS include sedation, ataxia and tremor. These symptoms occur infrequently and usually respond to a decrease in doses. Rash, alopecia and stimulation of appetite have been observed occasionally. Sodium Vaiproate has several effects on hepatic function of which elevation of liver enzymes in plasma is observed in up to 40% of patients and often occurs asymptomatically during the first few months of therapy. Rarely a fulminate hepatitis that may be fatal may develop. Children below 2 years of age with other medical conditions and those being treated with multiple antiepileptic agents are specially prone to suffer from hepatic injury, acute pancreatitis and hyperammonemia have also been frequently associated with the use of Sodium Valproate.

Sodium Valproate is contraindicated to patients who have known hypersensitivity to the drug and liver dysfunction. Use of Sodium Valproate is restricted during pregnancy and in women of childbearing potential.

Liver functions should be monitored before therapy and during first 6 months especially in patients most at risk, No undue potential for bleeding before starting and before major surgery must be ensured, Care should be taken in renal impairment, pregnancy, breast-feeding and systemic lupus erythematosus. Sodium Valproate is partially eliminated in the urine as a ketone metabolite, which may lead to a false interpretation of the urine ketone test. Sudden withdrawal of therapy should be avoided. Sodium Valproate should not be used during pregnancy and in women of childbearing potential.

Sodium Vaiproate appears to act as a non specific inhibitor of drug metabolism. Drugs to which it interacts most significantly are Phenobarbital, Phenytoin, Warfarin, Aspirin etc.

Sodium Vaiproate crosses the placenta and in humans, exposure to valproate in the first trimester has been associated with neural tube defects such as anencephaly and spina bifida in newborn. Pregnant women treated with Sodium Vaiproate should be offered to estimate serum a-fetoprotein. Sodium Valproate is excreted in breast miik. However, breast-feeding by a mother taking Sodium Valproate probably causes no risk to the child.

Do not store above 30°C. Keep away from light and out of the reach of children.

Primary anti-epileptic drugs

Sodium Valproate, the active ingredient of this preparation is endowed with anti-epileptic activity against a variety of seizures. The mechanism by which Sodium Valproate exerts its anti-epileptic effects has not been established. However, it has been suggested that its activity is related to increase brain levels of gamma-aminobutyric acid (GABA).

Sodium Valproate tablets may be given once or twice daily. Sodium Valproate syrup should be given in divided doses.

Epilepsy-

• Adults: Initially 600 mg daily given in 2 divided doses, preferably after food, increasing by 200 mg/day at 3-day intervals to a maximum of 2.5 g daily in divided doses until control of seizure is achieved. Usual maintenance dose is 1-2 g daily (20-30 mg/kg daily)
• Children (up to 20 kg): Initially 20 mg/kg daily in divided doses, may be increased provided plasma concentrations monitored (above 40 mg/kg daily also monitor clinical chemistry and hematological parameters).
• Children (over 20 kg): Initially 400 mg daily in divided doses increased until control (usually in the range of 20-30 mg/kg daily) Maximum 35 mg/kg daily.

Febrile convulsion: 20-30 mg/kg/day in 3 divided doses.

Bipolar disorder: Initially 20-30 mg/kg/day in 2-3 divided doses; adjust dosage in 3-5 days. Maintenance dosage is 1000-2000 mg/day.

Prophylaxis of migraine: 300 mg twice daily, although some may require 1000 mg daily.

The most common side effects are anorexia, nausea and vomiting. However, these side effects are minimized with the use of enteric coated tablets. Effects on the CNS include sedation, ataxia and tremor. These symptoms occur infrequently and usually respond to a decrease in doses. Rash, alopecia and stimulation of appetite have been observed occasionally. Sodium Vaiproate has several effects on hepatic function of which elevation of liver enzymes in plasma is observed in up to 40% of patients and often occurs asymptomatically during the first few months of therapy. Rarely a fulminate hepatitis that may be fatal may develop. Children below 2 years of age with other medical conditions and those being treated with multiple antiepileptic agents are specially prone to suffer from hepatic injury, acute pancreatitis and hyperammonemia have also been frequently associated with the use of Sodium Valproate.

Sodium Valproate is contraindicated to patients who have known hypersensitivity to the drug and liver dysfunction. Use of Sodium Valproate is restricted during pregnancy and in women of childbearing potential.

Liver functions should be monitored before therapy and during first 6 months especially in patients most at risk, No undue potential for bleeding before starting and before major surgery must be ensured, Care should be taken in renal impairment, pregnancy, breast-feeding and systemic lupus erythematosus. Sodium Valproate is partially eliminated in the urine as a ketone metabolite, which may lead to a false interpretation of the urine ketone test. Sudden withdrawal of therapy should be avoided. Sodium Valproate should not be used during pregnancy and in women of childbearing potential.

Sodium Vaiproate appears to act as a non specific inhibitor of drug metabolism. Drugs to which it interacts most significantly are Phenobarbital, Phenytoin, Warfarin, Aspirin etc.

Sodium Vaiproate crosses the placenta and in humans, exposure to valproate in the first trimester has been associated with neural tube defects such as anencephaly and spina bifida in newborn. Pregnant women treated with Sodium Vaiproate should be offered to estimate serum a-fetoprotein. Sodium Valproate is excreted in breast miik. However, breast-feeding by a mother taking Sodium Valproate probably causes no risk to the child.

Do not store above 30°C. Keep away from light and out of the reach of children.

Primary anti-epileptic drugs

Sodium Valproate, the active ingredient of this preparation is endowed with anti-epileptic activity against a variety of seizures. The mechanism by which Sodium Valproate exerts its anti-epileptic effects has not been established. However, it has been suggested that its activity is related to increase brain levels of gamma-aminobutyric acid (GABA).

Sodium Valproate tablets may be given once or twice daily. Sodium Valproate syrup should be given in divided doses.

Epilepsy-

• Adults: Initially 600 mg daily given in 2 divided doses, preferably after food, increasing by 200 mg/day at 3-day intervals to a maximum of 2.5 g daily in divided doses until control of seizure is achieved. Usual maintenance dose is 1-2 g daily (20-30 mg/kg daily)
• Children (up to 20 kg): Initially 20 mg/kg daily in divided doses, may be increased provided plasma concentrations monitored (above 40 mg/kg daily also monitor clinical chemistry and hematological parameters).
• Children (over 20 kg): Initially 400 mg daily in divided doses increased until control (usually in the range of 20-30 mg/kg daily) Maximum 35 mg/kg daily.

Febrile convulsion: 20-30 mg/kg/day in 3 divided doses.

Bipolar disorder: Initially 20-30 mg/kg/day in 2-3 divided doses; adjust dosage in 3-5 days. Maintenance dosage is 1000-2000 mg/day.

Prophylaxis of migraine: 300 mg twice daily, although some may require 1000 mg daily.

The most common side effects are anorexia, nausea and vomiting. However, these side effects are minimized with the use of enteric coated tablets. Effects on the CNS include sedation, ataxia and tremor. These symptoms occur infrequently and usually respond to a decrease in doses. Rash, alopecia and stimulation of appetite have been observed occasionally. Sodium Vaiproate has several effects on hepatic function of which elevation of liver enzymes in plasma is observed in up to 40% of patients and often occurs asymptomatically during the first few months of therapy. Rarely a fulminate hepatitis that may be fatal may develop. Children below 2 years of age with other medical conditions and those being treated with multiple antiepileptic agents are specially prone to suffer from hepatic injury, acute pancreatitis and hyperammonemia have also been frequently associated with the use of Sodium Valproate.

Sodium Valproate is contraindicated to patients who have known hypersensitivity to the drug and liver dysfunction. Use of Sodium Valproate is restricted during pregnancy and in women of childbearing potential.

Liver functions should be monitored before therapy and during first 6 months especially in patients most at risk, No undue potential for bleeding before starting and before major surgery must be ensured, Care should be taken in renal impairment, pregnancy, breast-feeding and systemic lupus erythematosus. Sodium Valproate is partially eliminated in the urine as a ketone metabolite, which may lead to a false interpretation of the urine ketone test. Sudden withdrawal of therapy should be avoided. Sodium Valproate should not be used during pregnancy and in women of childbearing potential.

Sodium Vaiproate appears to act as a non specific inhibitor of drug metabolism. Drugs to which it interacts most significantly are Phenobarbital, Phenytoin, Warfarin, Aspirin etc.

Sodium Vaiproate crosses the placenta and in humans, exposure to valproate in the first trimester has been associated with neural tube defects such as anencephaly and spina bifida in newborn. Pregnant women treated with Sodium Vaiproate should be offered to estimate serum a-fetoprotein. Sodium Valproate is excreted in breast miik. However, breast-feeding by a mother taking Sodium Valproate probably causes no risk to the child.

Do not store above 30°C. Keep away from light and out of the reach of children.

Primary anti-epileptic drugs

Sodium Valproate, the active ingredient of this preparation is endowed with anti-epileptic activity against a variety of seizures. The mechanism by which Sodium Valproate exerts its anti-epileptic effects has not been established. However, it has been suggested that its activity is related to increase brain levels of gamma-aminobutyric acid (GABA).

Sodium Valproate tablets may be given once or twice daily. Sodium Valproate syrup should be given in divided doses.

Epilepsy-

• Adults: Initially 600 mg daily given in 2 divided doses, preferably after food, increasing by 200 mg/day at 3-day intervals to a maximum of 2.5 g daily in divided doses until control of seizure is achieved. Usual maintenance dose is 1-2 g daily (20-30 mg/kg daily)
• Children (up to 20 kg): Initially 20 mg/kg daily in divided doses, may be increased provided plasma concentrations monitored (above 40 mg/kg daily also monitor clinical chemistry and hematological parameters).
• Children (over 20 kg): Initially 400 mg daily in divided doses increased until control (usually in the range of 20-30 mg/kg daily) Maximum 35 mg/kg daily.

Febrile convulsion: 20-30 mg/kg/day in 3 divided doses.

Bipolar disorder: Initially 20-30 mg/kg/day in 2-3 divided doses; adjust dosage in 3-5 days. Maintenance dosage is 1000-2000 mg/day.

Prophylaxis of migraine: 300 mg twice daily, although some may require 1000 mg daily.

The most common side effects are anorexia, nausea and vomiting. However, these side effects are minimized with the use of enteric coated tablets. Effects on the CNS include sedation, ataxia and tremor. These symptoms occur infrequently and usually respond to a decrease in doses. Rash, alopecia and stimulation of appetite have been observed occasionally. Sodium Vaiproate has several effects on hepatic function of which elevation of liver enzymes in plasma is observed in up to 40% of patients and often occurs asymptomatically during the first few months of therapy. Rarely a fulminate hepatitis that may be fatal may develop. Children below 2 years of age with other medical conditions and those being treated with multiple antiepileptic agents are specially prone to suffer from hepatic injury, acute pancreatitis and hyperammonemia have also been frequently associated with the use of Sodium Valproate.

Sodium Valproate is contraindicated to patients who have known hypersensitivity to the drug and liver dysfunction. Use of Sodium Valproate is restricted during pregnancy and in women of childbearing potential.

Liver functions should be monitored before therapy and during first 6 months especially in patients most at risk, No undue potential for bleeding before starting and before major surgery must be ensured, Care should be taken in renal impairment, pregnancy, breast-feeding and systemic lupus erythematosus. Sodium Valproate is partially eliminated in the urine as a ketone metabolite, which may lead to a false interpretation of the urine ketone test. Sudden withdrawal of therapy should be avoided. Sodium Valproate should not be used during pregnancy and in women of childbearing potential.

Sodium Vaiproate appears to act as a non specific inhibitor of drug metabolism. Drugs to which it interacts most significantly are Phenobarbital, Phenytoin, Warfarin, Aspirin etc.

Sodium Vaiproate crosses the placenta and in humans, exposure to valproate in the first trimester has been associated with neural tube defects such as anencephaly and spina bifida in newborn. Pregnant women treated with Sodium Vaiproate should be offered to estimate serum a-fetoprotein. Sodium Valproate is excreted in breast miik. However, breast-feeding by a mother taking Sodium Valproate probably causes no risk to the child.

Do not store above 30°C. Keep away from light and out of the reach of children.

Epinastine sterile ophthalmic solution is indicated for the treatment of signs and symptoms of allergic conditions of the anterior segment of the eye.

Ophthalmic Non-Steroid drugs

Epinastine is a topically active antihistamine that antagonizes both histamine H₁ and H₂ receptors. Moreover, it has mast cell stabilizing activity and prevents the release of inflammatory mediators from the blood vessel. Epinastine does not penetrate the blood-brain barrier and therefore is not expected to induce side effects on the central nervous system.

Instill 1 drop in the affected eye(s) twice daily.

The most frequently reported side effects are mild burning sensation, folliculosis, hyperemia, pruritus, cold symptoms and upper respiratory infections.

Contraindicated in patients who are hypersensitive to Epinastine or to any of the components of this preparation.

For ophthalmic use only. Patients should be advised not to wear contact lenses if their eye is red.

There are no adequate and well-controlled studies on pregnant women. Epinastine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether Epinastine is excreted in human milk. Caution should be exercised when Epinastine is administered to a nursing mother.

Use in children: Safety and effectiveness in children below the age of 3 years have not been established.

Use in elderly patients: No overall differences in safety and effectiveness have been observed between elderly and other adult patients.

Store in a cool & dry place, protect from light. Do not use longer than one month after the first opening. Keep out of the reach of children.

Epirubicin Injection is an anthracycline topoisomerase II inhibitor indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer

Cytotoxic Chemotherapy

Epirubicin, an anthracycline with cytotoxic properties. It inhibits DNA and RNA synthesis by steric obstruction after intercalating between DNA base pairs that triggers DNA cleavage by by topoisomerase II. It also inhibits DNA helicase and generates cytotoxic free radicals.

Acute leukaemias; Lymphoma; Multiple myeloma; Solid tumours:

• As a single agent: 60-90 mg/m² 3-4 wkly.
• Max (total cumulative dose): 0.9-1 g/m².
• Palliative care: 12.5-25 mg/m² once wkly.

Adjuvant treatment in axillary-node positive breast cancer: Recommended starting doses: 100-120 mg/m² as a single dose on day 1 or as 2 divided doses on days 1 and 8 of each 28-day cycle. Repeat for 6 cycles.

Intravesical Local treatment of bladder carcinoma: As 0.1% soln: 50 mg/wk for 8 wk; reduce dose if chemical cystitis develops.

For carcinoma in-situ: 80 mg in 50 mL wkly.

For prevention of recurrence in patients who have undergone transurethral resection: 50 mg/wk for 4 wk, followed by 50 mg/mth for 11 mth; retain soln in the bladder for 1 hr during each administration.

In early breast cancer, acute adverse events occurring in ≥10% of patients are leucopenia, neutropenia, anemia, thrombocytopenia, amenhorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local toxicity and rash/itch.

Long term adverse events occurring at a frequency of 1-2% are asymptomatic drops in LVEF and CHF and secondary leukemia.

Cardiac impairment, severe or recent Ml; previous full cumulative doses of anthracyclines. Hypersensitivity; severe hepatic dysfunction. Not for intravesical use where invasive tumours have penetrated the bladder wall; urinary infections, bladder inflammation or catheterisation problems. Pregnancy, lactation.

Previous extensive radiotherapy, bone infiltration by tumour, severe renal and hepatic dysfunction. May cause tumor lysis syndrome or radiation recall. Elderly women >70 yr. CV disease, hypertensive cardiomyopathy; monitor hematological and cardiac function regularly. Extravasation during IV admin may result in severe local tissue necrosis. Do not give via IM/SC routes as extravasation can lead to severe local necrosis

Paclitaxel and other anthracyclines. Cimetidine, heparin. Antineoplastic drugs, cardiotoxic drugs, radiation, hepatoactive drugs.

Discontinue nursing prior to taking Epirubicin. Not known if excreted in breast milk

Epirubicin Injection is an anthracycline topoisomerase II inhibitor indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer

Cytotoxic Chemotherapy

Epirubicin, an anthracycline with cytotoxic properties. It inhibits DNA and RNA synthesis by steric obstruction after intercalating between DNA base pairs that triggers DNA cleavage by by topoisomerase II. It also inhibits DNA helicase and generates cytotoxic free radicals.

Acute leukaemias; Lymphoma; Multiple myeloma; Solid tumours:

• As a single agent: 60-90 mg/m² 3-4 wkly.
• Max (total cumulative dose): 0.9-1 g/m².
• Palliative care: 12.5-25 mg/m² once wkly.

Adjuvant treatment in axillary-node positive breast cancer: Recommended starting doses: 100-120 mg/m² as a single dose on day 1 or as 2 divided doses on days 1 and 8 of each 28-day cycle. Repeat for 6 cycles.

Intravesical Local treatment of bladder carcinoma: As 0.1% soln: 50 mg/wk for 8 wk; reduce dose if chemical cystitis develops.

For carcinoma in-situ: 80 mg in 50 mL wkly.

For prevention of recurrence in patients who have undergone transurethral resection: 50 mg/wk for 4 wk, followed by 50 mg/mth for 11 mth; retain soln in the bladder for 1 hr during each administration.

In early breast cancer, acute adverse events occurring in ≥10% of patients are leucopenia, neutropenia, anemia, thrombocytopenia, amenhorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local toxicity and rash/itch.

Long term adverse events occurring at a frequency of 1-2% are asymptomatic drops in LVEF and CHF and secondary leukemia.

Cardiac impairment, severe or recent Ml; previous full cumulative doses of anthracyclines. Hypersensitivity; severe hepatic dysfunction. Not for intravesical use where invasive tumours have penetrated the bladder wall; urinary infections, bladder inflammation or catheterisation problems. Pregnancy, lactation.

Previous extensive radiotherapy, bone infiltration by tumour, severe renal and hepatic dysfunction. May cause tumor lysis syndrome or radiation recall. Elderly women >70 yr. CV disease, hypertensive cardiomyopathy; monitor hematological and cardiac function regularly. Extravasation during IV admin may result in severe local tissue necrosis. Do not give via IM/SC routes as extravasation can lead to severe local necrosis

Paclitaxel and other anthracyclines. Cimetidine, heparin. Antineoplastic drugs, cardiotoxic drugs, radiation, hepatoactive drugs.

Discontinue nursing prior to taking Epirubicin. Not known if excreted in breast milk

Epirubicin Injection is an anthracycline topoisomerase II inhibitor indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer

Cytotoxic Chemotherapy

Epirubicin, an anthracycline with cytotoxic properties. It inhibits DNA and RNA synthesis by steric obstruction after intercalating between DNA base pairs that triggers DNA cleavage by by topoisomerase II. It also inhibits DNA helicase and generates cytotoxic free radicals.

Acute leukaemias; Lymphoma; Multiple myeloma; Solid tumours:

• As a single agent: 60-90 mg/m² 3-4 wkly.
• Max (total cumulative dose): 0.9-1 g/m².
• Palliative care: 12.5-25 mg/m² once wkly.

Adjuvant treatment in axillary-node positive breast cancer: Recommended starting doses: 100-120 mg/m² as a single dose on day 1 or as 2 divided doses on days 1 and 8 of each 28-day cycle. Repeat for 6 cycles.

Intravesical Local treatment of bladder carcinoma: As 0.1% soln: 50 mg/wk for 8 wk; reduce dose if chemical cystitis develops.

For carcinoma in-situ: 80 mg in 50 mL wkly.

For prevention of recurrence in patients who have undergone transurethral resection: 50 mg/wk for 4 wk, followed by 50 mg/mth for 11 mth; retain soln in the bladder for 1 hr during each administration.

In early breast cancer, acute adverse events occurring in ≥10% of patients are leucopenia, neutropenia, anemia, thrombocytopenia, amenhorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local toxicity and rash/itch.

Long term adverse events occurring at a frequency of 1-2% are asymptomatic drops in LVEF and CHF and secondary leukemia.

Cardiac impairment, severe or recent Ml; previous full cumulative doses of anthracyclines. Hypersensitivity; severe hepatic dysfunction. Not for intravesical use where invasive tumours have penetrated the bladder wall; urinary infections, bladder inflammation or catheterisation problems. Pregnancy, lactation.

Previous extensive radiotherapy, bone infiltration by tumour, severe renal and hepatic dysfunction. May cause tumor lysis syndrome or radiation recall. Elderly women >70 yr. CV disease, hypertensive cardiomyopathy; monitor hematological and cardiac function regularly. Extravasation during IV admin may result in severe local tissue necrosis. Do not give via IM/SC routes as extravasation can lead to severe local necrosis

Paclitaxel and other anthracyclines. Cimetidine, heparin. Antineoplastic drugs, cardiotoxic drugs, radiation, hepatoactive drugs.

Discontinue nursing prior to taking Epirubicin. Not known if excreted in breast milk

Epirubicin Injection is an anthracycline topoisomerase II inhibitor indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer

Cytotoxic Chemotherapy

Epirubicin, an anthracycline with cytotoxic properties. It inhibits DNA and RNA synthesis by steric obstruction after intercalating between DNA base pairs that triggers DNA cleavage by by topoisomerase II. It also inhibits DNA helicase and generates cytotoxic free radicals.

Acute leukaemias; Lymphoma; Multiple myeloma; Solid tumours:

• As a single agent: 60-90 mg/m² 3-4 wkly.
• Max (total cumulative dose): 0.9-1 g/m².
• Palliative care: 12.5-25 mg/m² once wkly.

Adjuvant treatment in axillary-node positive breast cancer: Recommended starting doses: 100-120 mg/m² as a single dose on day 1 or as 2 divided doses on days 1 and 8 of each 28-day cycle. Repeat for 6 cycles.

Intravesical Local treatment of bladder carcinoma: As 0.1% soln: 50 mg/wk for 8 wk; reduce dose if chemical cystitis develops.

For carcinoma in-situ: 80 mg in 50 mL wkly.

For prevention of recurrence in patients who have undergone transurethral resection: 50 mg/wk for 4 wk, followed by 50 mg/mth for 11 mth; retain soln in the bladder for 1 hr during each administration.

In early breast cancer, acute adverse events occurring in ≥10% of patients are leucopenia, neutropenia, anemia, thrombocytopenia, amenhorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local toxicity and rash/itch.

Long term adverse events occurring at a frequency of 1-2% are asymptomatic drops in LVEF and CHF and secondary leukemia.

Cardiac impairment, severe or recent Ml; previous full cumulative doses of anthracyclines. Hypersensitivity; severe hepatic dysfunction. Not for intravesical use where invasive tumours have penetrated the bladder wall; urinary infections, bladder inflammation or catheterisation problems. Pregnancy, lactation.

Previous extensive radiotherapy, bone infiltration by tumour, severe renal and hepatic dysfunction. May cause tumor lysis syndrome or radiation recall. Elderly women >70 yr. CV disease, hypertensive cardiomyopathy; monitor hematological and cardiac function regularly. Extravasation during IV admin may result in severe local tissue necrosis. Do not give via IM/SC routes as extravasation can lead to severe local necrosis

Paclitaxel and other anthracyclines. Cimetidine, heparin. Antineoplastic drugs, cardiotoxic drugs, radiation, hepatoactive drugs.

Discontinue nursing prior to taking Epirubicin. Not known if excreted in breast milk

Epirubicin Injection is an anthracycline topoisomerase II inhibitor indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer

Cytotoxic Chemotherapy

Epirubicin, an anthracycline with cytotoxic properties. It inhibits DNA and RNA synthesis by steric obstruction after intercalating between DNA base pairs that triggers DNA cleavage by by topoisomerase II. It also inhibits DNA helicase and generates cytotoxic free radicals.

Acute leukaemias; Lymphoma; Multiple myeloma; Solid tumours:

• As a single agent: 60-90 mg/m² 3-4 wkly.
• Max (total cumulative dose): 0.9-1 g/m².
• Palliative care: 12.5-25 mg/m² once wkly.

Adjuvant treatment in axillary-node positive breast cancer: Recommended starting doses: 100-120 mg/m² as a single dose on day 1 or as 2 divided doses on days 1 and 8 of each 28-day cycle. Repeat for 6 cycles.

Intravesical Local treatment of bladder carcinoma: As 0.1% soln: 50 mg/wk for 8 wk; reduce dose if chemical cystitis develops.

For carcinoma in-situ: 80 mg in 50 mL wkly.

For prevention of recurrence in patients who have undergone transurethral resection: 50 mg/wk for 4 wk, followed by 50 mg/mth for 11 mth; retain soln in the bladder for 1 hr during each administration.

In early breast cancer, acute adverse events occurring in ≥10% of patients are leucopenia, neutropenia, anemia, thrombocytopenia, amenhorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local toxicity and rash/itch.

Long term adverse events occurring at a frequency of 1-2% are asymptomatic drops in LVEF and CHF and secondary leukemia.

Cardiac impairment, severe or recent Ml; previous full cumulative doses of anthracyclines. Hypersensitivity; severe hepatic dysfunction. Not for intravesical use where invasive tumours have penetrated the bladder wall; urinary infections, bladder inflammation or catheterisation problems. Pregnancy, lactation.

Previous extensive radiotherapy, bone infiltration by tumour, severe renal and hepatic dysfunction. May cause tumor lysis syndrome or radiation recall. Elderly women >70 yr. CV disease, hypertensive cardiomyopathy; monitor hematological and cardiac function regularly. Extravasation during IV admin may result in severe local tissue necrosis. Do not give via IM/SC routes as extravasation can lead to severe local necrosis

Paclitaxel and other anthracyclines. Cimetidine, heparin. Antineoplastic drugs, cardiotoxic drugs, radiation, hepatoactive drugs.

Discontinue nursing prior to taking Epirubicin. Not known if excreted in breast milk

Adjunct anti-epileptic drugs, Benzodiazepine hypnotics

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

There are also animal data showing an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.

Oral:

• Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

• The initial dose for adults with panic disorder is 0.25 mg given in two divided dose. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
• Pediatric Patients: In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

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.

The most frequently occurring side effects of Clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Abnormal eye movements, aphonia, coma, tremor, vertigo, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis & palpitations may also occur.

It should not be used in patients with a history of hypersensitivity to benzodiazepines, 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.

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. 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.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of Clonazepam on the metabolism of other drugs has not been investigated.

Pregnancy: From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines.

Nursing Mothers: Although the active ingredient of Clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Clonazepam, breastfeeding should be discontinued.

Pediatric Use: In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways. 

Geriatric Use: Benzodiazepine pharmacologic effects 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.

Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.

Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Clonazepam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment: Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

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.

Keep in a dry place away from light and heat. Keep out of the reach of children.

Adjunct anti-epileptic drugs, Benzodiazepine hypnotics

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

There are also animal data showing an effect of clonazepam on serotonin. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.

Oral:

• Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

• The initial dose for adults with panic disorder is 0.25 mg given in two divided dose. An increase to the target dose for most patients of 1 mg/day may be made after 3 days.
• Pediatric Patients: In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

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.

The most frequently occurring side effects of Clonazepam are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Abnormal eye movements, aphonia, coma, tremor, vertigo, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis & palpitations may also occur.

It should not be used in patients with a history of hypersensitivity to benzodiazepines, 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.

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. 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.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of Clonazepam on the metabolism of other drugs has not been investigated.

Pregnancy: From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines.

Nursing Mothers: Although the active ingredient of Clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Clonazepam, breastfeeding should be discontinued.

Pediatric Use: In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways. 

Geriatric Use: Benzodiazepine pharmacologic effects 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.

Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.

Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Clonazepam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment: Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug.

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.

Keep in a dry place away from light and heat. Keep out of the reach of children.