Effect of Topiramate (anticonvulsant) on Acid-base Balance

Student: Nasser Tajiani

II. Clinical Question: What is the mechanism of topiramate-induced metabolic acidosis?

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IV. Needs Assessment

(Outline, in detail, what has been done, what has not been done, and plan for completed project. In this section, you should be able to identify weaknesses and strengths of your 3 articles collectively, what further research you need to find, and where your shortcomings are.)

1. Clinicians who prescribe topiramate should be careful with possible adverse effects of topiramate (anticonvulsant and prophylaxis for migraine) produced as a result of its inhibition of carbonic anhydrase.
2. Based on the British Pharmacological Society (BJCP) in a retrospective cohort study conducted in an outpatient neurology clinic 48% of adult who were treated with topiramate for different medical conditions such as migraine, epilepsy, and vertigo had lower serum HCO3 – levels with topiramate treatment. In addition, another small group of nine children who were treated by Topiramate, eight children developed metabolic acidosis after 8-26 days (14 days median) of the Topiramate (TPM) treatment duration.
3. Additionally, in a retrospective cohort study conducted in an outpatient neurology clinic, 26 patients out of 54 (48%) had low serum HCO3- concentrations (<22 mEq l-1) while on topiramate.
4. The study suggests that patients who experience such adverse effects require discontinuation of treatment with topiramate and an alternative treatment option. However, if discontinuation is not possible, acid-base therapy in the form of alkali replacement should be considered.
5. There are several issues which are not covered in these studies. One issue is deficiency of identifying other potential risk factors, as well as longstanding significances of the acid base imbalance disturbance on metabolic, renal, and bone condition. Furthermore, not every study indicates the importance of routine serum HCO3- levels observation in patients on TPM therapy. Also, one of the studies which was done by the British Pharmacological Society (BJCP) is very small size of the nine trial children.
6. In addition, the epidemiological data exclude some patients who won’t develop acidosis with topiramate. Therefore there is uncertainty in such study whether the metabolic acidosis is the main cause and mechanism of patients’ symptoms. Dose can obviously be one predisposition cause of metabolic acidosis incidence by TPM overdosed patients. Although, most patients develop metabolic acidosis within the recommended therapeutic dosages anyways.
7. Another possibility is genetic polymorphisms in the genes for CA isoenzymes II, IV or XII may be predisposing factors, but this needs to be evaluated in a robustly phenotype cohort of patients on topiramate which is not done yet.
8. An additional research from Annals Pharmacotherapy discuss the fact that Topiramate chemical structure is a beta-D-fructopyranose sulfamate substituted monosaccharide that is unique to TPM in contrast to other antiepileptic medications. So, TPM mechanism of action is the inhibition of carbonic anhydrase activity which is linked to loss of bicarbonate from kidneys and subsequently metabolic acidosis or electrolyte imbalance.
   • Objectives: The objectives of the study were to investigate the influence of TPM therapy on bicarbonate and potassium levels in adult epileptic patients.
   • Method: Data were collected from total of 59 patients on monotherapy or co-therapy of TPM and other antiepileptic drugs with generalized or focal epilepsy, on regular follow-up with the following clinics; The Clinic of Neurology, Clinical Center of Serbia, and the University of Belgrade. The study involved male and female patients age of 18 years or older who had been using TPM for at least a week with available serum bicarbonate from all patients.
   • Result: Patients were divided into group A (duration of therapy shorter than or equal to 5 years) and group B (duration of therapy longer than 5 years).
   • Conclusions: Results highlight the frequent incidence of lower bicarbonate level associated with prolonged TPM therapy.

The issue with this study is the country of origin where the research was done is Europe which may not necessarily reflect the United States of America FDA regulation and standards.

• The Lancet Neurol article in Germany has done a relevant study for use of preventive therapy for migraine is often recommended for only 6-9 months, but no randomized, placebo-controlled trials have investigated migraine frequency after the end of prophylaxis. This research assessed the effects of discontinuation of topiramate after a treatment period of 6 months.
  • Methods: A randomized, double-blind, placebo-controlled trial of 818 patients who had migraine headaches were registered from 88 clinics within 21 different countries. After a 4-8 week preliminary period, patients received Topiramate in a 26 week open label stage. Patients’ initial dose of 25mg/day was increased up to 100mg/day in weekly 25mg increments. While the dose could be adjusted further in range of 50-200 mg/day, regardless every patient was stable for the last 4 weeks. Then patients were randomly selected either to stay on the final dose or change to placebo for the period of 26 weeks double blind phase.
  • Findings- The open label phase was completed by 559 (68.3%) of patients and 514 of patients went into double blind phase and were either allocated to TPM (n=255) or placebo (n=259). As a result there was an increase in days of patients having migraine compare to the placebo group of patients with confidence interval (CI) of 95% (0.71-1.66) and P value of <0.0001 than in the TPM group with CI of 92% (-0.36-0.56) and P value of 0.58.
  • Interpretation: Despite increasing number of migraine days after cessation of TPM, yet there was continued profit statement among patients. Such findings recommend and emphasis the maximum treatment period of 6 months and in some patients up to 12 months.

The advantage of this study in comparison to the others is the diversity in race and age of anticipants. These patients were enrolled from 88 neurology clinics in 21 countries in Europe and the Middle East. The trial requirement for qualified patients was the age of 18-80 years old whom satisfied International Headache Society (HIS) measures for migraine with or without sensory disturbance. As a result of this study, the Topiramate should not be prescribed for more than 6 months and in some cases up to 12 months. The effect of the Topamax as prophylaxis in migraine and for shorter period of time and metabolic acidosis effect of this medicine in another study support the adverse effect of Topamax long term use.

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V. Search Strategy

(Describe databases and terms utilized for search.)

I used multiple resources in peer reviewed and reliable sites such as PCT Madigan Library, Up-to-date, JStor, National Institutes of Health (NIH), British Journal of Clinical Pharmacology (BJCP), and Lancet Neurol where study was done in Europe and Middle East.

I used a current patient who was on long term use of Topamax with the following terms to find relevant topic and studies in regards to Topamax drug;

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• A female patient who presented in emergency department at a clinical site with N/V and got admitted without diagnosis.
• Can Topiramate cause nausea and vomiting?
• Topiramate and metabolic acidosis effect.
• Topiramate effect on acid-base disturbance.

VI. Studies for Review

(List at least TWO citations (articles) that you have reviewed on your topic. Please include hyperlinks to each article. You do not need to print each individual article for submission. Include a corresponding critique form for each article).

1. Mirza N, Mason GA & Pirmohamed M. Effect of Topiramate on acid-base balance: extent, mechanism and effects. British Journal of Clinical Pharmacology (BJCP), 2009; DOI:10.1111/j.1365-2125.2009.03521.x. Retrieved from; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791971/ PCT Madigan Library.
2. Dell’Orto VG., Belotti EA., & Goeggel-Simonetti B. et al. Metabolic disturbances and renal stone promotion on treatment with topiramate: a systematic review. British Journal of Clinical Pharmacology (BJCP), 2013; DOI:10.1111/bcp.12283. Up-to-date/PCT Madigan Library. Retrieved from; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093921/
3. Jovanović M, Sokić D, Grabnar I. et al. Effect of Long-term Topiramate Therapy on Serum Bicarbonate and Potassium Levels in Adult Epileptic Patients. Annals of Pharmacotherapy, 2014, Vol. 48(8) 992-997. Retrieved from Jstore; http://journals.sagepub.com/doi/abs/10.1177/1060028014534397
4. Diener HC., Agosti R, Allais G. et al. Cessation versus continuation of 6-month migraine preventive therapy with topiramate (PROMPT): a randomized, double-blind, placebo-controlled trial. Lancet Neurol 2007; 6: 1054-62

Retrieved from JStore, http://neurology.thelancet.com

5. Ganti M. M.D 2017, Director of the Sunbury Community Hospital, Emergency Department.

Evaluating articles about Etiology/Harm

Relevance:

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1. Did the authors study an outcome that patients would care about? YES NO

(Be careful to avoid results that require extrapolation to an outcome that truly matters to patients)

What is/are the outcome(s) studied?

1. Despite Topiramate benefit for migraine prevention, this study shows that chronic use of TPM causes acid-base balance disturbance in patient. Although, the Lancet Neurol study states that Topiramate chronic use more than 6 months result showed that patients who discontinued migraine preventive treatment with TPM had an increase in the number of migraine days compared with patients who continued treatment. However, acid-base change in some patients who were on long term preventative TPM use, result in nausea and vomiting and required discontinuation of Topiramate.
2. In another study done by, Annals of pharmacotherapy, 2014, results point out the frequent occurrence of lower bicarbonate level associated with prolonged TPM and other drugs therapy in patient with epilepsy. This study suggests that such patients’ bicarbonate to be monitored constantly if patient decided to continue TPM therapy.
3. In British Journal of Clinical Pharmacology (BJCP), 2009, Forty-seven reports published between 1996 and 2013 were retained for the final analysis. Five case-control studies and six longitudinal studies addressed the effect of topiramate on acid-base and potassium balance. According to this study result in regards to acid-base disturbance, there are two forms of metabolic acidosis change in patient, first cause is loss of Bicarbonate HCO3- from the GI tract most commonly due to diarrhea. Second major cause is a selective defect in renal H+/acid secretion or bicarbonate absorption. Both of the mentioned causes collectively called Renal Tubular Acidosis (RTA).

• Furthermore, according to the BJCP 2009 study, if chronic metabolic acidosis is left untreated, it can increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia or osteoporosis and consequently an increased risk for fractures. Additionally, chronic metabolic acidosis in children may also reduce growth rates.

2. Is the problem studied one that is common to your practice? YES NO

During my ER clinical rotation, my preceptor and I encounter a 59 y/o female who presented with c/c of N/V with metabolic acidosis finding by ABG test. Patient was admitted and the ER and consulted physicians and myself tried to follow up on this patient to find the cause of her metabolic acidosis. After two days research we realized that patient has been on prolonged TPM therapy over 5 years for the prevention of her migraine. Thus, her TPM treatment was discontinued and her condition improved subsequently.

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Validity:

1. Describe type of study (e.g. cohort, case-control)

1. Annals of pharmacotherapy, 2014, research observed metabolic acidosis in 48% of patient who were treated with TPM in a retrospective cohort study. Their data were obtained from 59 adult patients on monotherapy or co-therapy of TPM and other antiepileptic medicines (carbamazepine, phenobarbital, valproic acid, lamotrigine, levetiracetam, or pregabalin).
2. Lancet Neurol, 2007, study is based on the topiramate treatment in a randomized, double-blind, placebo controlled trial method that shows neurological risk in prolonged TPM therapy.
3. BJCP, 2009 study was done on five case-control studies and six longitudinal studies which addressed the effect of topiramate on acid-base (H+, HCO3-) and potassium (K+) balance.
4. In addition, British Journal of Clinical Pharmacology (BJCP), 2013 utilized reviews of the literatures, and Systematic Reviews and Meta-Analyses statement.
5. Ganti M. M.D 2017, Director of the Sunbury Community Hospital, Emergency Department.

2. Were there clearly identified comparison groups that were similar with respect to important determinants of outcome, other than the One of interest?

Explain whether groups were comparable. If not, describe why not.

Yes, in each study double-blind, placebo-controlled groups as well as different age groups from 18-80 years old, children, and diverse nationality and races were selected for these studies. For instance, in Lancet Neurol, 2007 study methods, 818 patients who all had migraines were enrolled in their study from 88 different clinics from 21 different countries.

3. Were the exposures and outcomes measured in the same way in the groups being compared?

Any evidence of recall or interviewer bias? If no bias, how did the researchers control against bias? If there was bias, describe:

The intention of these studies are focused on patient safety and best time frame use of Topiramate in patients with epilepsy, migraine, and depression. There is no evidence of any pharmaceutical influence or representation involvement in these studies. Furthermore, in compliance with the Unified Competing Interest (UCI) and approval of conflict of interest, all the above applied research studies authors have stated the completion of the UCI form and proclaim which can be viewed upon request from the author/authors at http://www.icmje.org/coi_disclosure.pdf.

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The proclamation indicates that the submitted studies have no funding and financial association from any group, governments or society that potentially might have attention or have predisposed the provided research work within last three years.

4. Was the exposure opportunity similar between groups?

YES NO Explain.

• In one study, 818 patients with migraine headaches were registered from 88 clinics in 21 different countries. After a 4-8 weeks period, patients received Topiramate in a 26-week open label period. Patients’ initial dose of 25mg/day was increased up to 100mg/day in weekly 25mg increments. While the dose could be adjusted further in range of 50-200 mg/day, regardless every patient was stable for the last 4 weeks. Then patients were randomly selected either to stay on the final dose or change to placebo for the period of 26 weeks double blind phase.

The selected patients within each group and phase were exposed either to medication or placebo equally with the same duration where the overall open label phase was completed by 559 (68.3%) of patients and 514 of patients went into double-blind phase and were either allocated to TPM (n=255) or control (n=259).Throughout the latter 4 weeks of the open label phase, the last dose of TPM was retained constant. The purpose of this phase was to achieve the starting values/dose for contrast and evaluation with the double-blind phase during the real progression of this experiment (Diener HC, Agosti R, Allais G. et al).

5. Was follow-up sufficiently long and complete? YES NO

1. Why or why not?

In the “Lancet Neurol 2007“, patients who adhered to the study protocol and received a TPM dose of 50-200 mg/day were eligible to enter the 26 week double- blind phase.

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Moreover, following the initial open-label and double-blind phases, patients were scheduled for the 4,8,16 and 26 weeks follow up visits and sequel. For the duration of this study, all patients groups as well as placebo’s health status and quality of life was attained and all the participants were steady and well balanced.

2. Were risk factors similar in those lost and not lost to follow-up? Describe.

In Lancet Neurol study, out of 818 patients with migraine, 68.3% were able to complete the open-label phase, thus 514 patients were entered the double-blind phase and the rest of 304 patients discontinued the study while they had the same risk factors as those who completed the study. In order to have a reliable result from all patients involved in study, the initial patients were selected based on their decent and stable health status so the risk factors in both groups will be the same.

As per 514 patients, n=255 were assigned to TPM therapy and n=259 were elected for placebo. As a result, those who discontinued the trial in comparison to those who completed the study in two groups of placebo and prolonged therapy with open-label, had the same neurological outcome. The primary endpoint patients were those who had increased number of days with migraine similar to those with placebo trial with the same neurological risk factors.

However, generally patients who are on chronic TPM therapy for any reason can have additional risk factors caused by metabolic acidosis that may include hyperventilation, nonspecific symptoms such as fatigue, anorexia, and more severe sequelae including cardiac arrhythmias or coma. Furthermore, if chronic metabolic acidosis is left untreated it can increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia or osteoporosis and consequently an increased risk for fractures. Chronic metabolic acidosis in children may also reduce growth rates.

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In Annals of Pharmacotherapy 2014, study caution was given specifically for those who are on TPM for lifetime which can lead to other present risk factors, such as respiratory, renal disease, ketogenic diet treatment, surgery, and systemic illnesses such as sepsis or shock.

6. Is the temporal relationship correct? YES NO Did the exposure precede the adverse outcome? In some studies adverse outcome could be noticed which determine diverse effect of TPM in each patient. However, majority of prolong TPM exposed patients did express adverse effect of electrolyte imbalance from the TPM. Despite the adverse outcome of prolong TPM treatment, there is no doubt that TPM does help and has persistent benefit to patients with migraines by preventing or minimizing the number of migraine occurrence. For instance, the Lancet Neuron 2007 study outcomes with its core focus on the neurological adverse effect showed that patients who discontinued their TPM migraine preventive treatment experienced a rise in migraine quantity in days and did not yield their pre-treatment values in contrast to patients who sustained their treatment.

The study suggests that patients should not be treated with TPM more than 6 months with the option of continuation up to 12 months in some selected patients.

In contrast, some studies demonstrated different results. For instance, no correlation was noted by Belotti et al, but duration of therapy was shorter, and the number of patients was smaller than the previous study.

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The British Journal of Clinical Pharmacology, 2009 conclude the importance of clinicians’ attention to possible adverse effects of TPM which is produced as a result of topiramate inhibition of carbonic anhydrase. This research suggests that patients who experience such adverse effects usually require discontinuation of treatment with topiramate, or therapy with another available anticonvulsant drug.

Meanwhile, Annals of Pharmacotherapy 2014, study concluded that TPM efficacy has to be balanced with its adverse effect profile. As multiple adverse effects which mostly were central nervous system related among patients with TPM therapy. The nervous system effects include dizziness, fatigue, and psychomotor slowing. Additionally, a number of adverse effects, related to inhibition of Carbonic anhydrase inhibitor, such as hyperventilation, nephrolithiasis, and change in mental status were observed.

7. Is there a dose-response gradient? YES NO

Does the risk of outcome increase with quantity or duration of exposure?

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Describe the relationship between outcome and exposure.

The Annals of Pharmacotherapy, 2014 research study with the title of “Effect of Long-term Topiramate Therapy on Serum Bicarbonate and Potassium Levels in Adult Epileptic Patients” is focused on medication exposure time and dosage. In this study patients were divided into two groups of A (duration of therapy 5 years). Significant difference (P < 0.05) in serum bicarbonate levels was observed between these 2 groups. Bicarbonate levels were linearly related to the TPM therapy duration and no correlation was found between the topiramate (TPM) dose or patient age and bicarbonate or potassium levels, as well as between therapy duration and potassium level. As a result, the study concluded that the frequent occurrence of lower bicarbonate level associated with prolonged TPM therapy. Thus, they suggested that patients’ bicarbonate levels on long-term TPM therapy should be monitored in order to keep the acid-base level of such patients balanced and neutral.

8. What are the results?

How strong is the association between exposure and outcome? Explain and give values.

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The systemic consequences of metabolic acidosis may be minor in some patients, but in the meantime clinically significant. Such consequences can include nausea, vomiting, anorexia, or paresthesia. In case of chronic condition, the outcome can be more serious in form of increased risk for nephrolithiasis, osteoporosis and osteomalacia.

The Annals of Pharmacotherapy, 2014 study which it’s data analysis was concluded in Chicago, IL based it’s focus on the length of TPM therapy by dividing patients into two groups of A and B. Next, calculation for performance as well as multiple analysis of the relation between the mean value of one variable production and corresponding values of other variables with the same time frame was considered in order to explore the correlation of TPM dose, treatment duration and patient age with measurement of the serum HCO3- and K+ level.

In this study, linear regression analysis was utilized in order to assess the relationship between TPM trough levels and serum bicarbonate or potassium levels. As a result the P value of <0.05 which shows 50/50 in the regression model, was an indication of a significantly connected element. In accordance to confirmation of such data’s measurement and legitimacy, the specific statistical analysis was checked and the result revealed remarkable (P<0.05) decreased bicarbonate levels in patients who were on TPM therapy for >5yrs in this study. However, not all patients with decreased bicarbonate levels showed symptoms which is an indication for TPM not being potent inhibitor for every patient.

Because TPM is not equally potent inhibitor of all carbonic anhydrase isoenzymes transcripts, not every patient shows low bicarbonate and other manifestations. Therefore, long term therapy has a great influence on this study outcome. Table-1 below shows the patients demographic and biochemical data of gender, age, weight, BMI, as well as serum bicarbonate, potassium and creatinine collected in this study. As a result, the final model of the multiple regression analysis incorporated the impact of TPM therapy interval on HCO3- level with a P value of (P<0.01).

The remaining of the final model was normally dispersed and standardized residuals which is the result of primarily modified between -2 and +2 values. In this study, serum bicarbonate level was used in the following equation;

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[BIC/Bicarb level (mmol / L) = 25 − 0.04 Ã- DTPM/Duration of TPM therapy (months)] to calculate the activity of TPM duration therapy which is shown in official Fig.1A table of this study report.

In addition, outcome of the British Journal of Clinical Pharmacology, 2013 indicated that in the final analysis of 47 reports which were published between period of 1996-2013, five case control studies as well as six longitudinal studies confirmed the effect of Topiramate on acid-base and potassium balance. This outcome represents a great inclination towards mild to moderate hyperchloremic metabolic acidosis which can result in nausea, vomiting, and other consequences in patients under prolonged TPM therapy.

The Lancet Neurol, 2007 has a different approach and outcome in their conclusion. This study concluded that TPM therapy definitely was beneficial to those who continued their treatment, while patients who discontinued the therapy got more migraine attacks. However, their findings offered 6 months with the maximum 12 months in some cases of TPM treatment in order to minimize the adverse effects of prolonged TPM therapy.

Similarly, BJCP, 2009 “effect of TPM on acid-base balance” suggests that increasing use of TPM as prophylaxis in migraine and epilepsy treatment as well as wide range of other indications, can impair the normal reabsorption of filtered HCO3- by the proximal renal tubule (PRT) type two as well as excretion of H+ by the distal renal tubule (DRT) type one renal tubular acidosis which in general such deficiencies is termed as mixed renal tubular acidosis (RTA) which is an uncommon renal disorder. Hence, this study suggests either discontinuation of TPM or substitution of topiramate with other similar drugs within the anticonvulsant group.

• How precise is the estimate of risk? (i.e., are confidence intervals provided?) Provide values.

In addition, to the results from multiple studies and researches done on cohort and longitudinal groups in regards to disturbance of acid-base balance with prolonged TPM therapy. One of the unique reason that Topiramate has been the center of research attention is that TPM is structurally different from other antiepileptic’s. Topiramate complex mechanism of action includes the blockade of voltage-gated Na+ channels which is similar to many other antiepileptic medications. Nonetheless, what is distinctive about Topiramate mechanism of action is the enrichment of gamma-aminobutyric acid receptor action and prevention of carbonic anhydrases which results in accumulation of carbonic acid in kidneys. Although, there is no known relation of mechanisms in function of TPM with other drugs in same group, yet there is no evidence that any other single antiepileptic drug has a similar structure with five specific properties.

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The systematic review of the studies and samples indicate that patient treatment with Topiramate as a broad-spectrum agent is relevant to moderate hyperchloremic metabolic acidosis. Such abnormalities are usually the consequence of inhibition of renal carbonic anhydrases which lead to tubular dysfunction.

Circulating bicarbonate, Cl- & K+ levels in patients on treatment with TPM for ≥3 months.

In the table above both case-control and longitudinal studies were included and the outcome are given as weighted means ± Standard Deviation (SD).

In this study evident increase of Cl- with P value <0.001 and decrease of K+ with P value of <0.001 was noticed in patients samples who were treated with TPM for 3 months or more.

Additionally, in another study which the open label phase was completed by 559 (68.3%) of patients, 514 of them went into double blind phase and were either allocated to TPM (n=255) or placebo (n=259). As a result there was an increase in days of patients having migraine compare to the placebo group of patients with confidence interval (CI) of 95% (0.71-1.66) and P value of <0.0001 than in the TPM group with CI of 92% (-0.36-0.56) and P value of 0.58.

9. Based on the evidence, would you attempt to stop the exposure to your patient?

YES NO

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• Is the evidence stro