Ramsoom 600mg film-coated tablets

Each film-coated tablet contains 600 mg gabapentin
For a full list of excipients, see section 6.1.

Film-coated tablet

4.1 Therapeutic indications
Epilepsy
Adults and children over 12 years,
Ramsoom is an anti-epileptic agent indicated as add-on therapy for partial  seizures (with or without secondary generalization) in patients who have not achieved satisfactory control with, or who exhibit intolerance to, standard anticonvulsants whether used alone or in combination.

Children 6 - 12 years of age
Ramsoom may be used as add-on therapy for partial seizures (with or without secondary generalization) in children aged between 6 - 12 years, who have not achieved satisfactory control with, or who exhibit intolerance to, standard anticonvulsants whether used alone or in combination, if the risk-benefit ratio is considered favorable. Treatment should be initiated and supervised by a neurological specialist.

Children under 6 years of age
The use of Ramsoom is not recommended in this age group owing to the lack of sufficient supporting data.

Neuropathic pain
Ramsoom is indicated for the treatment of neuropathic pain in adults.

4.2 Posology and method of administration
Epilepsy
Adults and children (over 12 years)Ramsoom tablets are administered orally, and may be taken with or without food.The anti-epileptic effect of Ramsoom generally occurs at a daily dose of 900 to 1200mg. it is not necessary to monitor Ramsoom plasma concentrations to optimize therapy.An effective dose can be achieved rapidly by titration over a few days, by administering 300mg once a day on the first day, 300 mg twice a day on the second day and 300 mg three times a day on the third day (refer to table 1 below)
Table 1: Dosing chart for initial titration

Dosage can be increased subsequently with increments of 300mg per day given in three equally divided doses, to a daily maximum of 2400mg. The maximum time between doses in a three times daily schedule should not be more than 12 hours.
Discontinuation of Ramsoom, and/or addition of an alternative anticonvulsant medicinal product to the treatment regimen, should be accomplished gradually over a minimum period of one week.

Elderly
Dosage adjustment may be necessary in elderly patients, due to declining renal function with age (refer to table 2)

Children 6 -12 years of age
The recommended dose of Ramsoom is 25mg/kg/day to 35mg/kg/day, given in divided doses three times a day. An effective dose can be achieved by titration over three days, by administering 10mg/kg/day on the first day, 20mg/kg/day on the second day and 25mg/kg/day to 35mg/kg/day on the third day. A suggested maintenance dosing schedule is given below:

Neuropathic pain
Adults (Over 18 years)
Ramsoom tablets are administered orally, and may be taken with or without food
Ramsoom should be titrated to a maximum dose of 1800mg per day.
An effective dose can be achieved rapidly by titration over a few days, by administering 300mg once a day on the first day; 300mg twice a day on the second day 300mg three times a day on the third day (refer to table 1)
Dosage can be increased subsequently with increments of 300 mg per day to daily maximum of 1800 mg, given in three divided doses. There is no need to divide the doses equally when titrating Ramsoom, and it is not necessary to monitor Ramsoom plasma concentration to optimize therapy.
The maximum time between doses in a three times daily schedule should not be more than 12 hours.
In the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia, efficacy and safety have not been examined in clinical studies for treatment periods longer than 5 months. If a patient requires dosing longer than 5 months for the treatment of peripheral neuropathic pain, the treating physician should assess the patient’s clinical status and determine the need for additional therapy.
Discontinuation of Ramsoom, dosage reduction or substitution with an alternative medicinal product, should be achieved gradually during a minimum period of one week.

Elderly
It may be necessary to adjust the dose in elderly patients, due to declining renal function with age (refer to table 2)

Patients with impaired renal function or undergoing haemodialysis
It is recommended that a dose adjustment is made for patients with impaired renal function and those undergoing haemodialysis. The dosage recommendations for impaired renal function are summarized in table 2 overleaf.For patients undergoing haemodialysis who have not previously been given ramsoom, a loading dose of 300 to 400 mg is recommended, with a further 200 to 300 mg of ramsoom following each 4 hours of haemodialysis.
Table 2: Maintenance dosage of Ramsoom in patients with impaired renal function

Dose:Total daily dose should be administered as a three times daily regimen for patients with normal renal function (Creatinin clearance>80 ml/min) , the daily dose will range from 900 - 2400 mg. Dosage reduction is recommended for patients with impaired renal function ( creatine clearance <79 ml/min). To be administered as 300mg on alternative days. For patients with creatinine clearance <15 ml/min, the daily dose should be reduced in proportion to Creatinin clearance (e.g. patients with a creatinine clearance of 7.5 ml/min should receive one-half the daily dose that patients with a creatinine clearance of 15 ml/min receive).

Use in patients undergoing haemodialysis
For anuric patients undergoing haemodialysis who have never received Ramsoom, a loading dose of 300 to 400 mg, then 200 to 300mg of Ramsoom following each 4 hours of haemodialysis, is recommended. On dialysis- free days, there should be no treatment with ramsoom.For renally impaired patients undergoing haemodialysis, the maintenance dose of Ramsoom should be based on the dosing recommendations found in table 2. In addition to the maintenance dose, an additional 200 to 300 mg dose following each 4 hours haemodialysis treatment is recommended.

4.3 contraindications
Hypersensitivity to the active substance Ramsoom, or to any of the excipients of Ramsoom tablets.

4.4 Special warnings and precautions for use
Although there is no evidence of rebound seizures with ramsoom, abrupt withdrawal of anticonvulsant agents in epileptic patients may be precipitate status epilepticus. When in the judgment of the clinician, there is a need for dose reduction, discontinuation or substitution of alternative anticonvulsants medicinal products; this should be affected gradually over a period of at least one week.
Ramsoom is not considered effective against primary generalized seizures such as absence and may aggravate these seizures in some patients. Therefore, Ramsoom should be used with caution in patients with mixed seizures including absences.
If a patient develops acute pancreatitis under treatment with Ramsoom, discontinuation of Ramsoom should be considered. As with other anti-epileptic medicinal products, some patients may experience an increase in seizure frequency or the onset of new types of seizures with Ramsoom. As with anti-epileptic, attempts to withdraw concomitant anti-epileptics in treatment refractive part on more than one antiepileptic, in order to reach Ramsoom monotherapy have a low success rate. No systematic studies in patients 65 years or older have been conducted with gabapentin. In one double blind study in patients with neuropathic pain, somnolence, peripheral oedema and asthenia occurred in a somewhat higher percentage in patients aged 65 years or above, than in younger patients. Apart from these findings, clinical investigations in this age group do not indicate an adverse event profile different from that observed in younger patients.
The effects of long term (greater than 36 weeks) gabapentin therapy on learning, intelligence, and development in children and adolescent have not been adequately studied. The benefits of prolonged therapy must therefore be weighed against the potential risks of such therapy.

Laboratory tests
Patients taking Ramsoom can be the subject of mood and behavioral disturbances. Such reports have been noted in patients receiving ramsoom, although a causal link has not been established.Caution is recommended in patients with a history of psychotic illness. On commencing treatment with ramsoom, psychotic episodes have been reported in some patients with and rarely without, a history of psychotic illness. Most of these events resolved when Ramsoom was discontinued, or the dosage reduced.

Suicide/suicidal thoughts:
Suicidal ideation and behavior have been reported in patients treated with anti-epileptic agent in several indications. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk of Ramsoom.
Therefore patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

4.5 Interaction with other medicinal products and other forms of interaction
When 60mg controlled release morphine capsule was administered 2 hours prior to a 600mg Ramsoom film coated tablet, mean Ramsoom AUC increased by 44 % compared to ramsoom administered without morphine. Therefore patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of ramsoom or morphine should be reduced appropriately.
The anticonvulsant effect of antiepileptics is antagonized by tricyclic antidepressants, selective – serotonin re-uptake inhibitors (SSRIs) and mefloquine, and maybe antagonized by monoamine oxidase inhibitors (MAOIs) and tricyclic-related antidepressants. There is a possibility of increased risk of convulsions when antiepileptic are given with chloroquine and hydroxychloroquine.
Ramsoom may be used in combination with other anti-epileptic medicinal products, without concern for alteration of the plasma concentrations of Ramsoom or the serum concentrations of other anti-epileptic active substances.
There are no interactions between ramsoom and phenytoin, valproic acid, carbamazepine or phenobarbitone. Steady state pharmacokinetics of ramsoom is similar in healthy subjects and in patients with epilepsy receiving antiepileptic agents.
Co-administration of ramsoom with oral contraceptives including norethisterone and/or ethinyl oestradiol dose not influence the steady-state pharmacokinetics of either component.
In a clinical study where Ramsoom was given at the same time as aluminum and magnesium containing antacid, the bioavailability of ramsoom was reduced by up to 24%. It is recommended that Ramsoom should be taken about two hours following any such antacid administration.
The renal excretion of Ramsoom is not altered by probencid, whereas a slight decrease in renal excretion of Ramsoom is observed when co-administered with cimetidine. However, this is not expected to be of clinical importance.
False positive readings have been reported with the Ames N-Multistix SG® dipstick test when Ramsoom was added to other anticonvulsant drugs. The more specific sulphosalicylic acid precipitation procedure is recommended to determine urinary protein.

4.6 Pregnancy and lactation
Risk related to epilepsy and antiepileptic medicinal products in general 
The risk of birth defects is increased by a factor of 2 - 3 in the offspring of mothers treated with an antiepileptic medicinal product. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practiced whenever possible. Specialist advice should be given to women who are likely to become pregnant or who are childbearing potential and the need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child. Development delay in children of mother with epilepsy has been observed rarely. It is not possible to differentiate if the developmental delay is caused by genetic, social factors, maternal epilepsy or the antiepileptic therapy.

Risk related to Ramsoom
There are no adequate data from the use of Ramsoom in pregnant women.
Studies in  animals have shown reproductive toxicity. The potential risk of humans is unknown.Ramsoom should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the fetus.
No definite conclusion can be made as to whether Ramsoom is associated with an increased risk of congenital malformations when taken during pregnancy, because of epilepsy itself and the presence of concomitant antiepileptic medicinal products during each reported pregnancy.
Ramsoom is excreted in human milk. Because the effect on the breast-fed infant 
is unknown, caution should be exercised when Ramsoom is administered to a 
breast-feeding mother. Ramsoom should be used in breast-feeding mothers only if the benefits clearly outweigh the risks.

4.7 Effects on ability to drive and use machines
Ramsoom acts on the nervous system and may produce drowsiness, dizziness, or related symptoms. Whilst these adverse events are otherwise mild or moderate, they pose a potential danger for patients who are driving or operating machinery, particularly until such time as the individual patient’s experience with Ramsoom is characterized. This is especially true at the beginning of the treatment and after increase in dose.

4.8 Undesirable effects
The adverse reactions observed during clinical studies conducted in epilepsy (adjunctive and monotherapy) and neuropathic pain have provided in a single list below by class and frequency (very common, common, uncommon and rare). Where an adverse reaction was seen at different frequencies in clinical studies, it was assigned to the highest frequency reported.
Additional reactions reported from the post-marketing experience are included as frequency not known (can not be estimated from the available data) Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations
Very common:          viral infection
Common: Pneumonia, respiratory infection, urinary tract infection, infection, otitis media

Blood and the lymphatic system disorders
Common: Leucopenia
Not known: Thrombocytopenia  

Immune system disorders 
Uncommon : Allergic reactions (e.g. urticaria)

Metabolism and nutrition disorders
Common : anorexia , increased appetite

Psychiatric disorders
Common: hostility, confusion and emotional lability, depression, anxiety, nervousness, thinking abnormal
Not known: hallucinations

Nervous system disorders
Very common: somnolence, dizziness, and ataxia
Common: convulsions, hyperkinesias, dysarthria, amnesia, tremors, insomnia, headache, sensations such as paraesthesia, hypaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes
Uncommon: hypokinesia
Not known: other movement disorders (e.g. choreoathetosis, dyskinesia, dystonia)

Eye disorders
Common: visual disturbances such as amblyopia, diplopia

Ear and labyrinth disorders
Common: vertigo
Not known: tinnitus

Cardiac disorders
Uncommon: palpitations

Vascular disorder
Common: hypertension, vasodilatation

Respiratory, thoracic and mediastinal disorders
Common: dyspnoea, bronchitis, pharyngitis, cough, rhinitis

Gastrointestinal disorders
Common: vomiting, nausea, dental abnormalities, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence
Not known: pancreatitis

Hepatobiliary disorders
Not known: hepatitis, jaundice

Skin and subcutaneous tissue disorders
Common: facial oedema, purpura most often described as bruises resulting from physical trauma, rash, pruritus, acne
Not known: stevens-johnson syndrome, angioedema, erythema multiforme, alopecia

Musculoskeletal, connective tissue and bone disorders
Common: arthralgia, myalgia, back pain, twitching
Not known: myoclonus

Renal and urinary disorders
Not know: acute renal failure, incontinence

Reproductive system and breast disorders
Common: impotence
Not known: breast hypertrophy, gynaecomastia

General disorders and administration site conditions
Very common: fatigue, fever
Common: peripheral oedema, abnormal gait, asthenia, pain, malaise, flu syndrome
Uncommon: generalized oedema
Not known: withdrawal reactions (mostly anxiety, insomnia, nausea, pains, sweating),  chest pain.
Sudden unexplained deaths have been reported where a causal relationship to treatment with ramsoom has not been established.

Investigations

• Common: WBC (white blood cell count) decreased, weight gain.
• Uncommon: elevated liver function tests SGOT (AST), SGPT (ALT) and bilirubin 
• Not known: blood glucose fluctuations in patients with diabetes
• Under treatment with Ramsoom cases of acute pancreatitis were reported.
• Injury and poisoning: Common: accidental injury, fracture & abrasion   
• Causality with Ramsoom is unclear.
• In patients on haemodialysis due to end-stage renal failure, myopathy with elevated creatine kinase levels has been reported.
  Respiratory tract infections, otitis media, convulsions and bronchitis were reported only in clinical studies in children. Additionally, in clinical studies in children, aggressive behaviour and hyperkinesias were reported commonly.
   

4.9 Overdose
Acute, life-threatening toxicity has not been observed in overdoses with Ramsoom of up to 49 grams.
Symptoms of overdose include dizziness, double vision, slurred speech, drowsiness, lethargy and mild diarrhea. All patients recovered fully with supportive care. Reduced absorption of Ramsoom at higher doses may limit drug absorption at the time of overdosing and thus minimize toxicity from overdoses.
Overdoses of Ramsoom, particularly in combination with other CNS depressant medications, may result in coma.
Although Ramsoom can removed by haemodialysis, based on prior experience it is not usually required. However, in patients with severe renal impairment, haemodialysis may be indicated.
An oral lethal dose of Ramsoom was not identified in mice and rats given doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, hypo-activity, or excitation.

5.1 Pharmacodynamic properties
The precise mechanism of action of Ramsoom is not known
Ramsoom is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but its mechanism of action is different from that of several other active substances that interact with GABA
synapses including valproate, barbiturate, benzodiazepines, GABA transaminase inhibitors, GABA uptake inhibitors, GABA agonists and GABA produrugs. In vitro studies with radiolabelled Ramsoom have characterized a novel peptide binding site in rat brain tissues including neocortex and hippocampus that may relate to anticonvulsant and analgesic activity of Ramsoom and its structural derivatives.
The binding site for Ramsoom has been identified as the alpha2 - delta subunit of voltage-gated calcium channels.
Ramsoom at relevant clinical concentrations does not bind to other common drug or neurotransmitter receptors of the brain including GABAa , GABAb, benzodiazepine, glutamate, glycine or N-methyl-d-aspartate receptors.
Ramsoom does not interact with sodium channels in vitro and so differs from phenytoin and carbamazepine. Ramsoom partially reduces responses to the glutamate agonist N-methyl-D-aspartate (NMDA) in some test systems in vitro, but only at concentrations greater than 100 µm, which are not achieved in vivo. Ramsoom slightly reduces the release of monoamine neurotransmitters in vitro.
Ramsoom administration to rats increases GABA turnover in several brain regions in a manner similar to valproate sodium, although in different regions of brain. The relevance of these various actions of Ramsoom to the anticonvulsant effects remains to be established. In animals, Ramsoom readily enters the brain and prevents seizures from maximal electroshock, from chemical convulsants including inhibitors of GABA synthesis, and in genetic models of seizures.
A clinical trial of adjunctive treatment of partial seizures in pediatric subjects ranging in age from 3 to 12 years, showed a numerical but not statistically significant difference in the 50% responder rate in favour of the Ramsoom group compared to placebo. Additional post-hoc analysis of the responder rates by age did not reveal a statistically significant effect of age, either as a continues or dichotomous variable (age group 3 - 5 and 6 - 12 years).
The data from this additional post-hoc analysis are summarized in the table below:

*The modified intent to treat population was defined as all patients randomized to study medication that also had evaluable seizure diaries available for 28 days during both the baseline and double-blind phases.

5.2 Pharmacokinetics properties
Absorption
Following oral administration, peak plasma gabapentin concentrations are observed within 2 to 3 hours.
Gabapentin bioavailability (fraction of dose absorbed) tends to decrease with increasing dose. Absolute bioavailability of a 300 mg capsule is approximately 60%. Food, including a high-fat diet, has no clinically significant effect on gabapentin pharmacokinetics.
Gabapentin pharmacokinetics are not affected by repeated administration. Although plasma gabapentin concentrations were generally between 2 µg/ml and 20 µg/ml in clinical studies, such concentrations were not predictive of safety or efficacy. Pharmacokinetics parameters are given in table 3.
Table 3
Summary of gabapentin mean (%CV) steady-state pharmacokinetics parameters following every eight hours administration

Based on the results of bioavailability studies performed with gabapentin tablets, 600 and 800mg tablets are bioequivalent to gabapentin capsules. 600mg gabapentin tablets were found to be bioequivalent to 2 x 300mg capsules based on a similar rate and extent of drug absorption. Likewise, 800mg tablets were found to be bioequivalent to 2 x 400mg capsules.
Distribution
Ramsoom is not bound to plasma protein and has a volume of distribution equal to 57.7 liters. In patients with epilepsy, ramsoom concentrations in cerebrospinal fluid (CSF) are approximately 20% of corresponding steady-state through plasma concentrations. Ramsoom is present in the breast milk of breast-feeding women.
Metabolism
There is no evidence of Ramsoom metabolism in humans. Ramsoom does not 
induce hepatic mixed function oxidase enzymes responsible for drug metabolism.
Elimination
Ramsoom is eliminated unchanged solely by renal excretion. The elimination 
half-life of Ramsoom is independent of dose and averages 5 to 7 hours.
In elderly patients, and in patients with impaired renal function, Ramsoom plasma clearance is reduced.
Ramsoom elimination-rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.
Ramsoom is removed from plasma by haemodialysis. Dosage adjustments in patients with compromised renal function or undergoing haemodialysis is recommended.
Ramsoom pharmacokinetics in children were determined in 50 healthy subjects between the ages of 1 month and 12 years. In general, plasma Ramsoom concentrations in children > 5 years of age are similar to those in adults when dosed on a mg/kg basis.
 

6.1 List of excipients
HPMC, Magnesium stearate, Avicel, Aerosil
Each coating contains: HPMC, Polyethylene glycol, Titanium dioxide, Talc powder

6.2 Incompatibilities
Not applicable

6.3 shelf life
2 years

6.4 special precautions for storage
Store in temperature not exceeding 30ºC, in dry place.

6.5 Nature and contents of container
Carton box containing one (AL/ Opaque PVC) strip of 10 film coated tablets.