1.TOPAMAX HISTORY
How was Topamax discovered?

Topamax is an anticonvulsant drug produced by Ortho-McNeil pharmaceutical.

Topamax received U.S. Food and Drug Administration (FDA) approval in March 1995.

Ortho-McNeil Neurologics is a division of Johnson & Johnson Corporation.

Note: World-drugs.net sells generic version of Topamax

2.TOPAMAX FACTS

Ortho-McNeil Pharmaceuticals currently markets products for Alzheimer's disease, epilepsy, and migraine prevention and treatment. Ortho-McNeil Neurologics continues to explore new opportunities to develop solutions for unmet health care needs in neurology in conjunction with internal and external research partners.

With more than 1,000 employees, Ortho-McNeil Neurologics is headquartered in Titusville, New Jersey.

3.ABOUT TOPAMAX MEDICATION
Topamax contains the active ingredient topiramate, which is a medicine that is used to treat epilepsy.

The brain and nerves are made up of many nerve cells that communicate with each other through electrical signals. These signals must be carefully regulated for the brain and nerves to function properly. When abnormally rapid and repetitive electrical signals are released in the brain, the brain becomes over-stimulated and normal function is disturbed. This results in fits or seizures.

Topamax works in three ways to prevent epileptic fits. Firstly, it enhances the activity of a neurotransmitter called GABA in the brain. Neurotransmitters are chemicals that are stored in nerve cells and are involved in transmitting messages between the nerve cells. GABA is a neurotransmitter that acts as a natural calming agent. It keeps the nerve activity in the brain in balance. As Topamax enhances the action of GABA, it helps calm the nerve activity in the brain.

WORKING OF TOPAMAX

Topamax also prevents sodium from entering the nerve cells when they begin to fire rapid and repetitive electrical signals. A build up of sodium in the nerve cells is necessary for the electrical signal to build up and be passed on. Topamax therefore prevents the excessive electrical activity that causes fits.

Topamax also decreases the ability of a neurotransmitter called glutamate to excite the nerve cells. It does this by blocking glutamate receptors.

All these actions calm the nerve cells and stabilize the electrical nerve activity in the brain. This helps prevent fits and maintain normal brain function.

Topamax can be used as an add-on treatment in adults and children over two years of age with epilepsy that has not been well controlled by the use of other antiepileptic medicines. It can also be used as a single treatment for adults and children over six years of age who have newly diagnosed epilepsy.

What is Epilepsy?

Epilepsy is a brain disorder in which clusters of nerve cells, or neurons, in the brain sometimes signal abnormally. In epilepsy, the normal pattern of neuronal activity becomes disturbed, causing strange sensations, emotions, and behavior or sometimes convulsions, muscle spasms, and loss of consciousness. Epilepsy is a disorder with many possible causes. Anything that disturbs the normal pattern of neuron activity - from illness to brain damage to abnormal brain development - can lead to seizures. Epilepsy may develop because of an abnormality in brain wiring, an imbalance of nerve signaling chemicals called neurotransmitters, or some combination of these factors. Having a seizure does not necessarily mean that a person has epilepsy. Only when a person has had two or more seizures is he or she considered having Epilepsy. EEGs and brain scans are common diagnostic test for Epilepsy.

Is there any treatment?

Once Epilepsy is diagnosed, it is important to begin treatment as soon as possible. For about 80 percent of those diagnosed with Epilepsy, seizures can be controlled with modern medicines and surgical techniques. Some antiepileptic drugs can interfere with the effectiveness of oral contraceptives. In 1997, the FDA approved the vagus nerve stimulator for use in people with seizures that are not well controlled by medication.

What is the prognosis?

Most people with Epilepsy lead outwardly normal lives. While Epilepsy cannot currently be cured, for some people it does eventually go away. Most seizures do not cause brain damage. It is not uncommon for people with Epilepsy, especially children, to develop behavioral and emotional problems, sometimes the consequence of embarrassment and frustration or bullying, teasing, or avoidance in school and other social setting. For many people with Epilepsy, the risk of seizures restricts their independence (some states refuse drivers licenses to people with Epilepsy) and recreational activities. People with Epilepsy are at special risk for two life-threatening conditions: status epilepticus and sudden unexplained death. Most women with Epilepsy can become pregnant, but they should discuss their Epilepsy and the medications they are taking with their doctors. Women with Epilepsy have a 90 percent or better chance of having a normal, healthy baby.

Antiepileptics or Anticonvulsants can be divided into older medications (called first-generation Anticonvulsants) and more recently developed medications (second-generation Anticonvulsants).

First-Generation Anticonvulsants

Phenytoin: This is one of the more commonly used agents and often is considered the first-line drug to treat partial and generalized tonic-clonic (grand mal) seizures and status epilepticus.

Phenytoin is thought to work by suppressing electrical activity in brain nerve cells. It can be given orally or intravenously (IV), and a newer form of the drug, fosphenytoin, can be injected into muscle. The oral form has the benefit of once-a-day dosing.

Carbamazepine : This drug is commonly prescribed for the treatment of partial and generalized tonic-clonic (grand mal) seizures. The mechanism by which it works is not well understood. In oral form, it can be taken 2 to 3 times a day; a recent development of the drug in sustained-release form allows for twice-a-day dosing.

Phenobarbital : This drug is used to treat both partial and generalized seizures. It also is used as part of the protocol after phenytoin use in status epilepticus as well as in neonatal epilepsy. It is available in oral and intravenous forms.

Valproate : This is prescribed for partial seizures, generalized tonic-clonic (grand mal) seizures, absence (petit mal) seizures, and myoclonic Epilepsy. Its mechanism of action is thought to be related to the effect of a brain substance known as GABA (gamma-aminobutyric acid). It is available in oral form and must be taken 2 to 3 times per day for adequate dosing.

Second-Generation Anticonvulsants

Topiramate : This drug is used with other anticonvulsant drugs in the treatment of partial seizures and generalized tonic-clonic seizures in adults and children aged 2 to 16. Its precise mechanism of action is unknown, but its anticonvulsant activity may be due in part to increasing GABA (gamma-aminobutyric acid), a neurotransmitter that inhibits excitation of nerve cells in the brain. It is available in oral form, including sprinkles for children, and is taken twice daily. There are few drug interactions between topiramate and other medications or other anticonvulsants.

Gabapentin : This drug is indicated for the adjunct treatment of partial seizures, with or without secondary generalization. Although it is structurally related to the substance GABA (gamma-aminobutyric acid), it does not interact with GABA receptors in the brain, and its mechanism of action is unknown. It is available in oral form and is taken 3 times daily.

Lamotrigine: This drug is used for the adjunct treatment of partial seizures. Its precise mechanism of action is unknown. It is presently available in oral form and is taken twice daily. No laboratory monitoring of drug levels are necessary.

Tiagabine: This drug is indicated for adjunct therapy in adults with partial seizures. Its mechanism of action may be related to its effect on the brain substance GABA (gamma-aminobutyric acid). It is available in oral form and should be given in divided doses 2 to 4 times daily. Its metabolism may be altered when taken with other anticonvulsants.

Levetiracetam : This drug is approved for use in adults as adjunct therapy for the treatment of partial seizure disorders. It is available in tablet form and as an oral solution for patients who prefer a liquid or cannot swallow tablets. Side effects of Topamax can include fatigue, imbalance, and behavioral changes, which often dissipate after the first month of treatment.

Oxcarbazepine : This drug is indicated for monotherapy (used alone) and adjunct therapy (in addition to other medications) in adults who have partial seizures and as adjunct therapy in children aged 4 and older who have partial seizures. When used as monotherapy, Trileptal causes very few of the side effects of Topamax associated with other AEDs.

Zonisamide : This drug is approved for use in adults as adjunct therapy for partial seizures. It has however, been used fairly extensively in other countries for use in other seizure types including generalized seizures, myoclonic seizures, and absence seizures. Patients who are allergic to sulfonamide drugs should not use zonisamide because it is a derivative of this class of drug.

Ethosuximide: This agent is used to treat absence (petit mal) seizures. It is thought to work by suppressing brain cell activity that is associated with lapses of consciousness. It is given orally and is available as a tablet or flavored syrup.

Primidone : This drug is a barbiturate that contains phenobarbitol. It is used to control generalized tonic-clonic (grand mal) seizures and partial seizures and is used in adults and children over 8 years old. Primidone is not known to interact with other drugs. It is present in breast milk and is associated with neonatal hemorrhage and coagulation defects similar to vitamin K deficiency. Patients hypersensitive to phenobarbital should not take primidone.

4.TOPAMAX EFFECTIVENES
When is Topamax best taken?

Absorption of Topamax is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 100 mg oral dose of Topamax. The relative bioavailability of topiramate from the tablet formulation is about 80%. The bioavailability of Topamax is not affected by food.

The pharmacokinetics of Topamax is linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours after single or multiple doses of Topamax. Steady state is thus reached in about 4 days in patients with normal renal function. Topamax is 13-17% bound to human plasma proteins over the concentration range of 1-250 µg/mL.

Metabolism and Excretion:

Topamax is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered doses of Topamax. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of Topamax. In rats, given probenecid to inhibit tubular reabsorption, along with Topamax, a significant increase in renal clearance of Topamax was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 to 30 mL/min in humans following oral administration.

5.TOPAMAX EFFECTS ON SPECIAL POPULATION
How do different people react to Topamax?

Age, Gender, and Race:

Clearance of Topamax in adults was not affected by age (18-67 years), gender, or race.

Pediatric Pharmacokinetics:

Pharmacokinetics of Topamax were evaluated in patients ages 4 to 17 years receiving one or two other antiepileptic drugs. Pharmacokinetic profiles were obtained after one week at doses of 1, 3, and 9 mg/kg/day. Clearance was independent of dose of Topamax.

Pediatric patients have a 50% higher clearance and consequently shorter elimination half-life than adults. Consequently, the plasma concentration for the same mg/kg doses of Topamax may be lower in pediatric patients compared to adults. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of Topamax.

6.TOPAMAX EFFECTS ON MEDICAL CONDITIONS
How does Topamax affect your existing condition/ailment?

Renal Impairment:

The clearance of Topamax was reduced by 42% in moderately renally impaired (creatinine clearance 30-69 mL/min/1.73m 2) and by 54% in severely renally impaired subjects (creatinine clearance <30 mL/min/1.73m 2) compared to normal renal function subjects (creatinine clearance >70 mL/min/1.73m 2). Since Topamax is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a clearance of Topamax not predicted by creatinine clearance. In general, however, use of one-half the usual dose of Topamax is recommended in patients with moderate or severe renal impairment.

Hemodialysis:

Topamax is cleared by hemodialysis. Using a high efficiency, counterflow, single pass-dialysate hemodialysis procedure, and Topamax dialysis clearance was 120 mL/min with blood flow through the dialyser at 400 mL/min. This high clearance (compared to 20-30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of Topamax from the patient over the hemodialysis treatment period. Therefore, a supplemental dose of Topamax may be required.

Hepatic Impairment:

In hepatically impaired subjects, the clearance of Topamax may be decreased; the mechanism underlying the decrease is not well understood.

7.OTHER/ALTERNATE USES OF TOPAMAX
What else does Topamax treat?

Topamax has been investigated for use in treatment of obesity, especially to aid in the reduction of binge eating, and also as a possible treatment for alcoholism.

8.ADVERSE/SIDE EFFECTS of TOPAMAX
What are the side effects of Topamax?

The most commonly observed adverse events associated with the use of Topamax at dosages of 200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in Topamax-treated patients and did not appear to be dose-related were:

The most common dose-related adverse events at dosages of 200 to 1,000 mg/day were:

Adverse events associated with the use of Topamax at dosages of 5 to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate -treated patients were:

In controlled clinical trials in adults, 11% of patients receiving Topamax 200 to 400 mg/day as adjunctive therapy discontinued due to adverse events. This rate appeared to increase at dosages above 400 mg/day.

Adverse events associated with discontinuing therapy included

None of the pediatric patients who received Topamax adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse events.

Approximately 28% of the 1,757 adults with Epilepsy who received Topamax at dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse events; an individual patient could have reported more than one adverse event.

Other Adverse events Observed During All Clinical Trials

Topamax, initiated as adjunctive therapy, has been administered to 1,757 adults and 310 pediatric patients with Epilepsy during all clinical studies. During these studies, all Adverse events were recorded by the clinical investigators using terminology of their own choosing. The frequencies presented represent the proportion of patients who experienced an event of the type cited on at least one occasion while receiving topiramate. Reported events are included except those already listed in the previous table or text, those too general to be informative, and those not reasonably associated with the use of the drug.

Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent occurring in at least 1/100 patients; infrequent occurring in 1/100 to 1/1000 patients; rare occurring in fewer than 1/1000 patients.

Autonomic Nervous System Disorders :

Infrequent : vasodilation.

Body as a Whole:

Frequent : fever. Infrequent: syncope, abdomen enlarged.

Rare : alcohol intolerance.

Cardiovascular Disorders, General:

Infrequent : hypotension, postural hypotension.

Central & Peripheral Nervous System Disorders:

Frequent : hypertonia.

Infrequent : neuropathy, apraxia, hyperaesthesia, dyskinesia, dysphonia, scotoma, ptosis, dystonia, visual field defect, encephalopathy, upper motor neuron lesion, EEG abnormal.

Rare : cerebellar syndrome, tongue paralysis.

Gastrointestinal System Disorders:

Frequent : diarrhea, vomiting, hemorrhoids.

Infrequent: stomatitis, melena, gastritis, tongue edema, esophagitis.

Hearing and Vestibular Disorders:

Frequent : tinnitus.

Heart Rate and Rhythm Disorders:

Infrequent : AV block, bradycardia.

Liver and Biliary System Disorders :

Infrequent : SGPT increased, SGOT increased, gamma-GT increased.

Metabolic and Nutritional Disorders:

Frequent : dehydration.

Infrequent : hypokalemia, alkaline phosphatase increased, hypocalcemia, hyperlipemia, acidosis, hyperglycemia, hyperchloremia, xerophthalmia.

Rare : diabetes mellitus, hypernatremia, hyponatremia, hypocholesterolemia, hypophosphatemia, creatinine increased.

Musculoskeletal System Disorders:

Frequent : arthralgia, muscle weakness.

Infrequent : arthrosis.

Myo-, Endo-, Pericardial & Valve Disorders:

Infrequent : angina pectoris.

Neoplasms:

Infrequent : thrombocythemia.

Rare: polycythemia.

Platelet, Bleeding, and Clotting Disorders:

Infrequent : gingival bleeding, pulmonary embolism.

Psychiatric Disorders :

Frequent: impotence, hallucination, euphoria, psychosis.

Infrequent : paranoid reaction, delusion, paranoia, delirium, abnormal dreaming, neurosis, libido increased, manic reaction, suicide attempt.

Red Blood Cell Disorders:

Frequent : anemia.

Rare : marrow depression, pancytopenia.

Reproductive Disorders, Male:

Infrequent : ejaculation disorder, breast discharge.

Skin and Appendages Disorders:

Frequent : acne, urticaria. Infrequent: photosensitivity reaction, sweating decreased, abnormal hair texture.

Rare : chloasma.

Special Senses Other, Disorders:

Infrequent: taste loss, parosmia.

Urinary System Disorders:

Frequent : dysuria, renal calculus.

Infrequent : urinary retention, face edema, renal pain, albuminuria, polyuria, oliguria.

Vascular (Extracardiac) Disorders:

Infrequent : flushing, deep vein thrombosis, phlebitis.

Rare : vasospasm.

Vision Disorders:

Frequent : conjunctivitis.

Infrequent : abnormal accommodation, photophobia, strabismus, mydriasis.

Rare : iritis.

White Cell and Reticuloendothelial System Disorders:

Infrequent : lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia, lymphocytosis.

9. USEFUL SITES

http://www.fda.gov

http://www.jnj.com

http://www.orthomcneil.com