METHOTREXATE
`
`0889-857X/97 $0.00 + .20
`
`THE USE OF FOLATES
`
`CONCOMITANTLY WITH LOW-
`
`DOSE PULSE METHOTREXATE
`
`Jeffrey B. Shiroky, MD, FRCP(C)
`
`Over the past 15 years, methotrexate therapy for rheumatic diseases
`has evolved from a role as treatment for ”intractable” inflammatory
`polyarthritis, to frequently the first choice of slow-acting remittive agents
`in early rheumatoid arthritis (RA). As rheumatologists have gained more
`experience with methotrexate, they have come to appreciate its quick
`and effective anti—inflammatory properties relative to alternative agents
`and the low incidence of serious toxicity. As a result, its uses have
`widened to other inflammatory rheumatic and nonrheumatic conditions,
`often in a role as a corticosteroid-sparing agent.
`Experimentation,
`largely by dermatologists, led to the low-dose,
`weekly, oral or intramuscular methotrexate therapy now used for rheu-
`matic diseases. It has been shown that titrating the dose of methotrexate
`between 5 mg and 20 mg weekly is associated with increasing anti-
`inflammatory activity.°' 3° Experiments with higher-dose regimens have
`suggested efficacy of methotrexate where standard therapy has failed.‘
`39' 4° Unfortunately, higher doses of methotrexate also result in a higher
`frequency and severity of adverse events.‘’'“'
`Despite the low frequency of serious toxicity with the standard
`regimen, there exist several side effects that limit methotrexate's use in
`certain patients or result in unwanted interruptions of therapy or a
`failure to titrate the dose optimally. For the most part, these adverse
`effects are the result of methotrexate’s antifolate properties (e.g., hemato-
`logic, mucositic, and hepatic complications; alopecia). Oncologic proto-
`
`From the Department of Rheumatic and Immunologic Diseases, Cleveland Clinic Florida,
`Fort Lauderdale, Florida
`
`RHEUMATIC DISEASE CLINICS OF NORTH AMERICA
`
`VOLUME 23 - NUMBER 4 - NOVEMBER 1997
`
`969
`
`Lilly Ex. 2087
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2087
`Sandoz v. Lilly IPR2016-00318
`
`

`
`970
`
`SHIROKY
`
`cols using extremely high doses of intravenous methotrexate (510 g) are
`well tolerated because of the concomitant use of folinic acid (leucovorin,
`citrovorum factor).’~ 1‘ In addition, repetitive high doses of folinic acid
`have been used to reverse serious acute methotrexate toxicity.‘ “~ 3° These
`observations have led to the evaluation of various folate regimens to
`reduce the frequency or dampen the severity of adverse events associ-
`ated with the low-dose weekly methotrexate therapy for rheumatic
`diseases.
`
`Essentially, there are two choices of agent to be used potentially as
`a folate supplement concomitantly with methotrexate: folic acid and
`folinic acid. Both have been evaluated in clinical trials and are used
`
`anecdotally in various ways. For folic acid to be effective, it must be
`able to compete with methotrexate as a substrate for dihydrofolate
`reductase so that it will be properly reduced to the biologically active
`form of folate necessary in the one carbon metabolism required in
`biosynthesis of certain amino acids (serine, methionine), de novo purine
`synthesis, and thymidine. In contrast, folinic acid (calcium 5-formyltet-
`rahydrofolate) is a pharmaceutically synthesized, relatively stable, fully
`reduced form of folate developed to treat and prevent toxicity related to
`methotrexate therapy. Because it is fuHy reduced, it bypasses the inhibi-
`tion of dihydrofolate reductase by methotrexate.‘ ‘* 1” Given that it is
`synthetic and does not have as wide a use as folate in the general
`population, the cost per pill of folinic acid when compared to folate is
`substantial.
`
`THE USE OF FOLIC ACID SUPPLEMENTS WITH
`METHOTREXATE
`
`Although given the oncologic experience, folinic acid would be the
`logical choice as supplemental therapy when methotrexate is used in
`the rheumatic patient, there have been proponents of folate for several
`reasons. First, concern has existed that folinic acid would build up in
`polyglutamated stores of intracellular folate and lead to methotrexate
`resistance. Indeed, concerns have even existed regarding acute resistance
`as well. Second, there has been concern that there exists an enormous
`cost difference between folic acid therapy and folinic acid therapy.
`Finally, it has been argued by the same advocates of folic acid that it is
`safer and more convenient.“
`
`At this time, there has been no clinical trial comparing folic acid
`versus folinic acid in this setting. Differences in study designs render
`meta-analyses unreliable. There have been no cost-benefit analyses to
`justify a recommendation that any given folate regimen be used at the
`inception of methotrexate therapy in all patients. There have been stud-
`ies showing effectiveness of both folic acid and folinic acid in reducing
`side effects related to low-dose weekly methotrexate therapy.
`The first successful placebo-controlled study was reported by Mor-
`gan and colleagues using 1 mg of folic acid daily.“ Based on a toxicity
`
`Lilly Ex. 2087
`Sandoz V. Lilly IPR20l6-00318
`
`Lilly Ex. 2087
`Sandoz v. Lilly IPR2016-00318
`
`

`
`THE USE OF FOLATES CONCOMITANTLY WITH LOW-DOSE PULSE METHOTREXATE
`
`971
`
`score developed by these investigators but never formally validated,
`they demonstrated that the folic acid supplementation was associated
`with lower toxicity scores and did not seem to interfere with the anti-
`inflammatory effects of methotrexate. Most importantly, this study did
`confirm that those with preexisting folate deficiency were more likely to
`experience methotrexate toxicity, and during therapy the mean cor-
`puscular volume (MCV) tended to rise in the placebo group. There were
`no differences between groups in the complete blood count or serum
`liver function tests, however. This study had a number of flaws. First, it
`was a small study (32 patients in total) and all of the difference between
`the two study groups could be accounted for by only four patients.
`Second, the methotrexate regimen did not reflect current use: A median
`of 7.5 mg of methotrexate was used, which is lower than the usual
`median (between 10 mg and 12 mg weekly) which subsequently tended
`to rise even higher.‘ '7' ‘° This raises a question about the efficacy of 1
`mg of folate daily with commonly used higher doses of methotrexate.
`The investigators used three doses of methotrexate weekly (q12hr) and
`not single-dose therapy (currently used). Finally, the study was only 6
`months long, suffering perhaps from being too short in duration because
`the highest dose of methotrexate employed may have been achieved
`only a few weeks before the end of the study. Prior use of methotrexate
`was allowed, if not in the preceding 6 months, providing a potential for
`selection bias or influence on the types and frequency of side effects.
`To further elucidate the value of folic acid supplementation, these
`same investigators conducted a second controlled trial, this time compar-
`ing placebo to 27.5 mg of folic acid weekly (5.5 mg daily for 5 days) and
`5 mg of folic acid weekly (1 mg daily for 5 days)?‘ No folic acid was
`given the day of methotrexate therapy or the day after, suggesting that
`the investigators were concerned with the potential of daily folic acid
`inducing methotrexate resistance. This latter point was not discussed,
`although the investigators once again raised concerns regarding the
`potential for folinic acid (leucovorin) to induce methotrexate resistance.
`All folate-containing vitamins were stopped at study entry.
`This study included more patients and had better power statistics
`based on their toxicity score, however. In addition, it lasted 48 weeks,
`thus being long enough to allow for the development of side effects,
`achieve optimal disease control, and observe for methotrexate resistance.
`The study did show that folic acid at either close was associated with
`lower toxicity scores without interfering with the anti-inflammatory
`benefits of methotrexate. The higher dose of folic acid was associated
`with more of a reduction in the toxicity score. Curiously, although there
`was a significant reduction in the frequency of side effects between
`placebo and the lower folic acid group, there was no statistically signifi-
`cant reduction between placebo and the higher dose of folic acid. In fact,
`the frequency of side effects in the higher folic acid group was higher
`than the lower folic acid group. The difference in toxicity scores between
`the two folic acid doses was accounted for by only two patients.
`Other problems exist with this study.“ First, the median dose of
`
`Lilly Ex. 2087
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2087
`Sandoz v. Lilly IPR2016-00318
`
`

`
`972
`
`SHIROKY
`
`methotrexate (8.5 mg versus 9.6 mg, placebo to high-dose folate, respec-
`tively) is still lower than the current use. Thus, it still is not known how
`this regimen would fare at higher doses of methotrexate. The study
`lacked in its design the adjusting of folic acid doses when methotrexate
`toxicities developed. As a result, also unknown is whether the addition
`of folic acid once toxicity occurs or an increase in folic acid when toxicity
`occurs would be effective. This needs to be emphasized because these
`investigators recommend increasing doses of folic acid to control or
`reverse side effects. In addition, no differences in blood counts or serum
`liver function tests were noted between groups. Finally, concern exists
`regarding how much folic acid was actually received by those in the
`two nonplacebo groups. The investigators initially intended to study
`placebo versus 5 mg versus 50 mg. It was discovered during the study
`that in fact the higher dose group was receiving a lower dose as the
`result of a manufacturing error. The study medications (placebo and
`folic acid) were prepared at the study center as identical capsules. The
`bioavailability of this preparation when compared dose per dose with
`commercially available folate supplements is therefore unknown.
`Two further studies are noteworthy. The first is a retrospective
`study of 200 patients with RA.“ All but two patients received about 7
`mg of folic acid as a total weekly dose. These patients were followed for
`a mean of 41.5 months. The authors’ primary conclusion was that an
`elevated MCV in this group was found in 21% and was not a significant
`predictor of hematologic or other side effects, with the exception of
`heartburn. Of note, the incidence of any side effect during the study
`was virtually universal, with moderate to severe side effects (severity
`score 2-4) occurring at some point in over 20% of their patients. When
`the patients were compared with their own historical controls not on
`folate, significant reductions in gastrointestinal symptoms, stornatitis,
`and elevated liver function tests were noted. Unfortunately, these histori-
`cal controls were neither well defined nor adequately contrasted against
`the folate group with respect to clinical variables. Furthermore, the mean
`dose of methotrexate was low by today's standards (8.5 mg/ wk).
`The second study was also retrospective and examined a group of
`158 patients with RA receiving methotrexate followed 24 hours later by
`5 mg of folic acid. Patients were followed up to 4 years. On this therapy,
`side effects were common (60%) and caused cessation of therapy in 90%
`of the cases. Only 25% of patients ceased methotrexate at 2 years,
`however, and discontinuation seemed to plateau thereafter.” This folate
`regimen is intriguing in that all the folate was given as a single dose
`weekly, unlike the Morgan study, which spread the same dose of folate
`(5 mg) over 5 days?" 1" As with the Morgan study, administration of
`folate was delayed, suggesting the same concern by the investigators
`(i.e., that folate taken at the same time as methotrexate might interfere
`with anti-inflammatory effects).
`Unfortunately, no study to date has determined whether 1 mg folic
`acid daily supplements are better than a simple multivitamin, containing
`
`Lilly Ex. 2087
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2087
`Sandoz v. Lilly IPR2016-00318
`
`

`
`THE USE OF FOLATES CONCOMITANTLY WITH LOW-DOSE PULSE NIETHOTREXATE
`
`973
`
`the recommended daily requirement of 400 ug folic acid. In the United
`States, 140 ug folic acid per 100 gm soon will be a nutritional supplement
`in all grains and cereals, providing a further source of this agent.
`
`THE USE OF FOUNIC ACID (LEUCOVORIN)
`SUPPLEMENTS WITH METHOTFIEXATE
`
`Anecdotal reports of the use of folinic acid with methotrexate date
`back almost 20 years.5' 315'’ These reports did not note significant negative
`effects of the addition of the folinic acid. A multitude of dosing schemes
`subsequently have been reported; unfortunately, most of these studies
`lacked scientific validity and did not evolve from the oncologic experi-
`ence.
`
`The first study evaluated the administration of 45 mg of folinic acid
`between 4 and 6 hours after methotrexate. This 4-week study involved
`only seven patients. The mean dose of methotrexate was 9.6 mg (7.5 mg-
`12.5 mg) or 20% of the folinic acid dose. Not surprisingly, all the benefits
`of methot:rexate were abrogated by such a high dose of folinic acid
`following so closely after the administration of methotrexate.” A similar
`outcome occurred in another study that used 15 mg of folinic acid given
`2 hours after a mean dose of 7.9 mg methotrexate." No folic acid study
`has attempted to give such high doses of folate so soon after methotrex-
`ate to see whether it would also abrogate the benefits of methotrexate.
`The first attempt to use a delayed folinic acid regimen in a clinical
`trial was performed by Hanrahan and Russell.“ Patients taking a mean
`of 18 mg methotrexate, who were about to discontinue methotrexate
`because of side effects, were given 2 daily doses of 10 mg folinic acid
`beginning at least 3 days after the methotrexate. Of the 13 patients
`enrolled, 11 had nausea as the major side effect of methotrexate. This
`study was placebo controlled with a crossover design, having two 4-
`week study periods. The investigators did not see any negative effect
`on inflammation. In the other folinic acid studies already discussed,
`flares occurred by 4 weeks. Although there was considerable improve-
`ment of nausea in patients, folinic acid could not be distinguished from
`lacebo.
`P
`There are several problems with this study. First, the study lacked
`a washout period, thus there could have been carryover effects of folinic
`acid into the placebo period of the study when folinic acid was given in
`the first period. Second, the administration of folinic acid at least 3 days
`after the administration of methotrexate could have been too long a
`delay, as it would be in the oncologic experience, which used folinic
`acid rescue preventively with high-dose intravenous methotrexate.’~ 1‘ "
`In addition, the sample size is too small and the study duration possibly
`too short to distinguish both positive and negative effects of the addition
`of folinic acid.
`'I'his author became interested in the use of folinic acid with low-
`
`dose weekly methotrexate while studying high-dose methotrexate (500
`
`Lilly Ex. 2087
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2087
`Sandoz v. Lilly IPR2016-00318
`
`

`
`974
`
`SHIROKY
`
`mg/In‘) intravenously followed 24 hours later by four doses of 15 to 25
`mg/m2 folinic acid given q6hr.3": 4° Thirteen patients were treated with
`this regimen for 2 to 6 months, and it was striking how well tolerated it
`was. All patients enrolled had previously failed standard methotrexate
`therapy, yet all the patients demonstrated improvement in their arthritis.
`This experiment used a standard high-dose oncologic regimen, delaying
`the folinic acid 24 hours after the methotrexate and giving it in lower
`milligram amounts.‘ 12- “ Of some concern in this study was one patient,
`who, during the first 8 weeks of therapy was considered an excellent
`responder, but who subsequently flared and became unresponsive to
`further treatments. This occurrence raised a concern that a buildup of
`folinic acid intracellularly eventually led to methotrexate resistance;
`however, this possibility or other known cellular mechanisms for metho-
`trexate resistance could not be formally studied in this patient.
`Over a period of 3 years, this author and colleagues experimented
`by treating side effects to low-dose methotrexate with folinic acid sup-
`plements. Drawing on previous high-dose experience, we delayed the
`folinic add 24 hours after the methotrexate and gave it in lower amounts.
`At that time, only 5-mg tablets were available and it was found that
`between 2.5 mg and 5 mg of folinic acid seemed enough for most
`situations. Of particular interest, this regimen was capable of normaliz-
`ing elevated transaminase levels, even when they were as high as ten
`times the upper limit of normal, over at least a two-month period. The
`continued use of folinic acid allowed the continuation of methotrexate
`
`at the same dose and in several cases higher doses.“
`Subsequently, we proceeded to a parallel-arm double-blind placebo-
`controlled trial to evaluate our regimen.” To date, it is the largest single
`controlled trial of folates with methotrexate and the only multicenter
`one. Unlike the folic acid study,” a commercially available folinic acid
`was employed (Leucovorin, Lederle, Pearl River, NY). This controlled
`trial is distinct from the folate studies on several accounts. First, we
`allowed and encouraged investigators to use methotrexate at the full
`range of oral doses currently used to achieve a clinical response (7.5
`mg—3O mg) and thus successfully achieved a mean dose of methotrexate
`of almost 13 mg, highly reflective of the current use. As a result, we
`gained experience with our folinic acid regimen over the full methotrex-
`ate dose range. Second, the h
`thesis was not that rheurnatologists
`were interested simply in using olate supplements prophylactically, but
`that they would also be interested in strategies to reduce or reverse side
`effects to methotrexate that were either preventing optimization of dos-
`ing or resulting in the discontinuation of therapy. Thus, our study
`actually was designed to test a strategy of using folinic acid to reduce
`the frequency of side effects and to reverse any that developed (Table
`1). The gold standard for the management of side effects that developed
`in this study was the reduction or withholding of methotrexate until
`resolution of the side effect. To this was added folinic acid or placebo in
`a double-blind randomized fashion. The primary outcome was the rate
`of success in eradicating side effects in each study arm. Patients with
`
`Lilly Ex. 2087
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2087
`Sandoz v. Lilly IPR2016-00318
`
`

`
`THE USE or FOLATES CONCOMITANTLY WITH LOW-DOSE PULSE METHOTREXATE
`
`975
`
`Table 1. PROPOSED METHOTREXATE AND FOLINIC ACID PROTOCOL
`
`
`Starting Dose of Follnlc Acid:
`Doses of methotrexate from 5.0—12.5 mg. Use 25 mg folinic acid as a single dose the
`day after methotrexate.
`Doses of methotrexate from 15-30 mg. Use 5.0 mg folinic acid as a single dose the day
`after methotrexate.
`
`Management of Methotrexate Toxicity
`Ilild side effects: Reduce methotrexate dose by 2.5 mg and use folinic acid at the
`above dose, until the complaint resolves. If no resolution. escalate management as
`described below for more intense side effects. Once side effects have resolved. resume
`previous dose of methotrexate and continue increasing as needed.
`Moderate side effects: withhold methotrexate’ until the reaction has resolved. with
`resolution, restart methotrexate at a dose 5.0 mg lower and if not on folinic acid start it.
`if patient is on folinic acid, use an additional 2.5 mg of ioilnlc acid (< 15 mg. use 5 mg
`of folinic acid; > 15 mg, use 5 mg and. if necessary, 7.5 mg, then 10 mg). If no
`immediate recurrence of the side effect (e.g.. after 2-3 doses). then resume the Initial
`dose of methotrexate and increase as necessary.
`Severe side effects: It side effects are potentially life threatening or patient requires
`hospitalization. stop methotrexate and use standard folinic acid rescue protocols to
`reverse. Once side effects have resolved. reevaluate treatment options and, it
`methotrexate is necessary and the patient has not been on folinic acid prior to the
`toxicity. use the above moderate side effect recommendation and monitor patient
`closely.
`
`unresolved side effects or those who failed to respond to methotrexate
`were deemed treatment failures and withdrawn, having achieved a
`study endpoint. The study was designed to follow atients for 52 weeks
`(1 year), allowing for an adequate time for side e ects or methotrexate
`resistance to develop. Prior methotrexate use was an exclusion criterion.
`Ninety-seven patients were enrolled, of whom ninety-two were
`evaluable (44 on folinic acid; 48 on placebo). Of those patients with
`persistent reports of side effects failing to respond to this treatment
`design (and thus withdrawn), 17 were in the placebo group and 5 were
`in the folinic acid group. Overall there was a 50% reduction in the
`reporting of side effects, a 60% reduction in elevated transaminase levels,
`and a 63% reduction in reports of moderate to severe gastrointestinal
`complaints when folinic acid was used. The MCV was higher in the
`placebo group when compared with the folinic acid group. In those
`completing 52 weeks of treatment, there was no difference in all disease
`activity measures between study groups. Only one patient failed to
`respond to methotrexate (defined as at least a 50% improvement in one
`of eight clinical variables) while receiving 30 mg of methotrexate. This
`patient was in the folinic acid arm. Although it has been suggested that
`this methotrexate failure was possibly due to folinic acid, it should be
`remembered that such a failure occurred in one patient only and the
`frequency of methotrexate failure in this study is in fact lower than that
`observed in other studies with or without folate supplements. Thus it is
`doubtful that this regimen of folinic acid induces clinically significant
`methotrexate resistance.
`
`Lilly Ex. 2087
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2087
`Sandoz v. Lilly IPR2016-00318
`
`

`
`976
`
`SHIROKY
`
`Of more interest was the observation that this folinic acid protocol
`reduces the frequency and can also reverse transaminase level eleva-
`tions; this was not observed in either of the controlled folic acid trials.
`Research has suggested an association between hepatic folate deficiency
`and methotrexate hepatotoxicity.“’- '3’ 25 This raises the possibility of
`a particular advantage in using folinic acid as opposed to folic acid
`prophylactically in those patients receiving methotrexate who are at
`increased risk for hepatic disease.
`~
`Two other regimens of folinic acid are worthy of noting. First,
`Buckley conducted a 48-week placebo—controlled trial of folinic acid
`given 4 hours after methotrexate in equivalent milligram doses.‘ Al-
`though there was a trend for reduced side effects with folinic acid, this
`did not achieve statistical significance. This study enrolled only 20 pa-
`tients, however, thus lacking any statistical power. It also enrolled pa-
`tients already on methotrexate for a mean of 9 to 10 months, thus biasing
`the study in favor of a reduced likelihood to develop side effects and
`therefore better methotrexate tolerability than would generally be ex-
`pected. Of interest, however, was that folinic acid with this dose sched-
`ule did not flare the rheumatoid disease. This latter observation has
`
`been tempered recently by a report of Buckley's regimen inducing
`disease flares in all three patients with juvenile RA tested.”
`The other report by Weinblatt showed that the simultaneous admin-
`istration of 1 mg of folinic acid over 8 weeks failed to result in disease
`flares.“ The study was too small and too short to draw any other
`conclusion, however.
`Unfortunately, none of the folinic acid or folic acid studies were
`large enough to draw conclusions regarding a benefit with respect to
`pancytopenias and pneumonitis, although both treatment regimens were
`shown to affect MCV. Severe pancytopenias are treated with folinic acid
`rescue.‘ 3”‘ In addition, although we have used up to 10 mg of folinic
`acid 24 hours after methotrexate (dosed >17.5 mg), these higher doses
`of folinic acid were not tested in a controlled trial.
`
`USE OF FOLATE SUPPLEMENTS
`
`At this time, a scientifically proven definitive recipe does not exist.
`Direct comparisons between folic acid and folinic acid do not exist.
`Investigators continue to evaluate new and different methotrexate regi-
`mens and new and different folinic acid regimens. Some conclusions
`from the literature can be drawn to form a rational plan for the present,
`however.
`
`.
`
`No current folate supplementation protocol is 100% effective at
`either preventing or resolving side effects. When all the existing litera-
`ture related to the use of methotrexate in rheumatic diseases is exam-
`
`ined, a large proportion of patients tolerate methotrexate without side
`effects. In the absence of cost—benefit studies, it cannot be recommended
`that all patients receiving methotrexate should also receive supplements
`
`Lilly Ex. 2087
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2087
`Sandoz v. Lilly IPR2016-00318
`
`

`
`THE USE OF FOLATE5 CONCOMITANTLY WITH DOW-DOSE PULSE METHOTREXATE
`
`977
`
`of folate as defined in the above studies. It is known that generally
`patients with RA have been shown to be deficient in several vitamins
`and minerals?’ "I "' Z9’ 3”’ Anemias developing in rheumatoid patients
`can be multifactorial.’°- 27' 3°' 31' "7 In light of these facts, all patients should
`be told of the need for a proper balanced diet. Fully recognizing that
`this is often difficult to achieve, a daily multivitamin with 400 pg folic
`acid (RDA) should be recommended. Unfortunately, it is not known
`whether 1 mg folic acid supplements are more effective than such
`multivitamins. In menstruating women, the multivitamin also should
`include iron. Whether iron should be taken by all patients is unknown
`but would seem reasonable for those with inadequate diets and possibly
`the elderly. In those demonstrating low folate levels at the onset of
`methotrexate therapy, 1 mg of folate should be given daily. Unless the
`particular problem that resulted in the deficiency can be corrected, folate
`at this dose should be continued. Subclinical folate and vitamin B12
`deficiencies are common in elderly patients and in some may be identi-
`fied only by measuring serum methylmalonic acid or homocysteine
`levels." 1” This should be done prior to methotrexate therapy, which
`alters homocysteine levels.25"‘3' 3‘ In those requiring methotrexate and
`who are also at increased risk for hepatic disease, folinic acid should be
`used prophylactically.
`Once a side effect is reported and seems to persist, the author's
`preference is the previously described folinic acid regimen because it is
`the only one demonstrated to be effective in this situation. This author
`has used up to 10 mg of folinic acid at the higher end of methotrexate
`doses without problem (17.5 mg-30 mg). In case of mild gastrointestinal
`symptoms try folate first. It is extremely important to emphasize that
`other factors may contribute to or cause the symptoms being attributed
`to methotrexate, especially gastrointestinal complaints (e.g., concurrent
`NSAIDs, antiulcer, or osteoporotic therapies).
`There remain the issues of cost and convenience between folinic
`
`acid and folic acid. In countries where only 1-mg tablets of folic acid are
`available, taking up to 5 tablets of folic acid daily in addition to all other
`concurrent therapy seems less appetizing than taking 1/2 or 1 tablet of
`folinic acid weekly. There is no doubt that 1 tablet of folic acid can be
`as much as 1/40 the cost of one 5-mg tablet of folinic acid; however,
`when one adds up the total tablets required monthly for both regimens,
`especially at the higher dose supplements, the cost differential is not
`that extreme. In the United States, the difference in cost between a
`month's worth of folate and a month's worth of folinic acid is between
`
`$5 and $15. It has been reported that in certain Latin American and
`European countries the folinic acid protocol described previously can
`cost the same or even less than the folic acid protocol, depending on
`how many tablets are used monthly (Personal communication)?-‘ What-
`ever the difference in monthly cost between folic acid and folinic acid,
`it is substantially smaller than the difference in cost between NSAIDS or
`antiulcer agents, especially when generic agents are considered. This is
`
`Lilly Ex. 2087
`Sandoz V. Lilly IPR20l6-00318
`
`Lilly Ex. 2087
`Sandoz v. Lilly IPR2016-00318
`
`

`
`978
`
`SHIROKY
`
`also true between sources of methotrexate (Personal communication:
`pharmacies, medication plans, and distributors, 1996).
`
`SUMMARY
`
`Toxicities related to low-dose weekly methotrexate are largely due
`to its antifolate properties. Preexisting folate deficiency is associated
`with methotrexate toxicity in some patients. At the onset of methotrexate
`therapy and throughout therapy, the physician should be vigilant re-
`garding one or more nutrient deficiencies. A multivitamin and, where
`appropriate, specific daily folic acid supplements should be employed.
`The only regimen known presently (through controlled trials) to treat
`side effects is the low-dose folinic acid (leucovorin) protocol outlined
`herein. Folic acid may be helpful to treat mild gastrointestinal symptoms.
`Folinic acid supplementation should be considered prophylactically in
`those requiring methotrexate who are at increased risk of hepatic dis-
`ease. Other possible factors besides methotrexate should always be con-
`sidered with the onset of new patient complaints or laboratory abnor-
`malities. Claims that folic acid therapy is safer and more convenient
`than folinic acid seem unwarranted when one reviews the literature
`carefully. Cost differences between folic acid supplementation and foli-
`nic acid supplementation have been exaggerated.
`
`References
`
`9’
`
`1. Allen RH, Stabler SP, Savage DG, et al: Diagnosis of cobalamin deficiency: L Usefulness
`of serum methylmalonic acid and total homocysteine. Am] Hematol 34:90, 1990
`2. Bleyer WA: Clinical pharmacology and therapeutic drug monitoring of methotrexate.
`Am Assoc Clin Chem 6:1, 1985
`Bolla G, Disdier P, Harle ]'R, et al: Concurrent acute megaloblastic anaemia and
`pneumonitis: A severe side effect of low-dose methotrexate therapy during rheumatoid
`arthritis. Clin Rheumatol 12:535, 1993
`Buckley LM, Vacek PM, Cooper SM: Administration of folinic acid after low-dose
`methotrexate in patients with rheumatoid arthritis. I Rheumatol 17:1158, 1990
`Burkhart CG: ‘Treatment of psoriasis with methotrexate and folinic acid. ] Am Acad
`Dermatol 3:207, 1980
`Furst DE, Koehnke R, Burmeister LF, et al: Increasing methotrexate effect with increas-
`ing dose in the treatment of resistant rheumatoid arthritis. ] Rheumatol 16:313, 1989
`Gabriel S, Creagan E, O’Fallon WM, et al: Treatment of rheumatoid arthritis with
`higher dose intravenous methotrexate. J Rheumatol 17:460, 1990
`Hanrahan PS, Russell AS: Concun-mt use of folinic acid and methotrexate in rheuma-
`toid arthritis. J Rheumatol 15:1078, 1988
`Hansson L, Huunan-Seppala A, Matilla A: The content of calcium, magnesium, copper,
`zinc, lead and chromium in blood of patients with rheumatoid arthritis. Scand J
`Rheumatol 4:33, 1978
`I-laurani Fl, Smukler N, Atwater I: Combined deficiency anemia in chronic disease.
`Ann Clin Lab Sci 2:161, 1972
`11. Honkanen VE: The factors affecting plasma glutathione peroxidase and selenium
`in rheumatoid arthritis: a multiple linear regression analysis. Scand J Rheumatol
`20:385. 1991
`
`Id.°}°.°°.\l?‘.U':F
`
`Lilly Ex. 2087
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2087
`Sandoz v. Lilly IPR2016-00318
`
`

`
`THE USE OF FOLATES CONCOMITANTLY WITH LOW-DOSE PULSE MFTHOTREXATE
`
`979
`
`-dose methotrexate
`
`12.
`
`I—|ID
`
`16.
`
`17.
`
`Isacoff W1-I, Morrison PF, Aroesty J, et al: Pharmacoltinetics of high
`with citrovorum factor rescue. Cancer Treat Rep 6l:l665, 1977
`. Jobanputra P, Hunter M, Clark D, et al: An audit of methotrexate and folic acid for
`rheumatoid arthritis: Experience from a teaching centre. Br] Rheumatol 34:97], 1995
`. Jolivet I, Cowan KH, Curt GA, et al: The pharmacology and clinical use of methotrex-
`ate. N Engl I Med 309:1094, 1983
`. Joyce DA, Will RK, Hoffman DM, et al: Exacerbation of rheumatoid arthritis in
`patiaits treated with methotrexate after administration of folinic acid. Ann Rheum Dis
`502913, 1991
`Kremer JM, Calivan I, Sreckfuss, et al: Methotrexate metabolism analysis in blood and
`liver of rheumatoid arthritis patients: Association with hepatic folate deficiency and
`formation of polyglutamates. Arthritis Rheum 29:832, 1986
`Kremer IM, Phelps CT: Long-term prospective study of