Glatiramer acetate: successful desensitization for
`treatment of multiple sclerosis
`
`Sonia N. Bains, MD *; Fred H. Hsieh, MD *1; Mary R. Rensel, MD$; Cristine Radojicic, MD *;
`Hary T. Katz, MD §; S. Rubina Inamdar, MD11; and David M. Lang, MD*
`
`Background: Glatiramer acetate is an immunomodulatory drug that is widely prescribed for the treatment of multiple
`sclerosis. It is frequently associated with local injection site reactions and generalized urticaria. It is also associated with
`immediate postinjection systemic reactions in approximately 10% of patients. To our knowledge, no desensitization protocols for
`glatiramer acetate have been published to date.
`Objectives: To evaluate the safety and efficacy of glatiramer acetate desensitization in a series of patients with multiple
`sclerosis.
`Methods: Six patients with multiple sclerosis and glatiramer acetate -associated local or systemic reactions underwent a 4 -hour
`outpatient desensitization procedure at Cleveland Clinic between 2003 and 2008. Beginning with 20 ng, we administered
`subcutaneous glatiramer acetate suspension in increasing dosages every 15 minutes. Patient outcomes were monitored by return
`clinic visit and telephone follow -up.
`Results: No episodes of anaphylaxis or serious adverse reactions occurred during or immediately after desensitization. One
`patient suspended therapy after 14 months due to persistent local injection site reactions. All other patients successfully continued
`glatiramer acetate therapy.
`Conclusion: Glatiramer acetate offers significant benefit to patients with multiple sclerosis. Our experience suggests that
`patients who suspend its use owing to local or systemic reactions can be successfully and safely desensitized and can resume
`medication use. To our knowledge, this is the first report of successful desensitization to glatiramer acetate in patients with
`multiple sclerosis.
`
`Ann Allergy Asthma Immunol. 2010;104:321 -325.
`
`INTRODUCTION
`Glatiramer acetate (Copaxone; Teva Neuroscience, Kansas
`City, Missouri) is a pool of synthetic peptides composed of
`random sequences of 4 amino acids: L- alanine, L- lysine,
`L- glutamic acid, and L- tyrosine. Its composition is based on
`the amino acid structure of myelin basic protein. Glatiramer
`acetate injection is supplied as a single -use syringe prefilled
`with 1.0 mL of a clear, colorless solution containing 20 mg of
`glatiramer acetate, 40 mg of mannitol, and no preservative.
`The recommended dose for the treatment of multiple sclerosis
`(MS) is 20 mg injected subcutaneously daily.
`Glatiramer acetate is one of the immunomodulatory drugs
`approved and widely prescribed for the treatment of MS,1-3 a
`chronic disorder that affects the brain, spinal cord, and optic
`nerve and is the leading cause of nontraumatic disability in
`
`Affiliations: * Department of Allergy and Immunology, Respiratory In-
`stitute, Cleveland Clinic, Cleveland, Ohio; f Department of Pathobiology,
`Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; $ The Mellen
`Center Department of Neurology, Cleveland Clinic, Cleveland, Ohio; § Di-
`vision of Pulmonary /Allergy and Immunology, Nemours Children's Clinic,
`Jacksonville, Florida; and ¶ Mercy Medical Group, Sacramento, California.
`Disclosures: Authors have nothing to disclose.
`Funding Sources: This study was supported by the William O. Wagner,
`MD, Research and Education Fund.
`Received for publication July 16, 2009; Received in revised form October
`14, 2009; Accepted for publication November 12, 2009.
`© 2010 American College of Allergy, Asthma & Immunology.
`Published by Elsevier Inc. All rights reserved.
`doi:10.1016 /j.anai.2009.11.040
`
`young adults.' Glatiramer acetate has been shown to signifi-
`cantly reduce the relapse rate and slow the progression of
`neurologic disability in patients with MS.' The drug has a
`favorable adverse effect profile compared with other medi-
`cations used to treat MS, including high -dose corticosteroids
`and interferon beta .4 However, approximately 50% of pa-
`tients may develop local injection site reactions, even though
`patients are instructed to rotate injection sites regularly. Up to
`10% of patients may experience immediate postinjection
`systemic reactions characterized by flushing, chest pain, pal-
`pitations, anxiety, dyspnea, throat constriction, and urticaria,
`which may preclude further glatiramer acetate administration
`due to the severity of the reaction.4 This poses an obstacle to
`the treatment of MS, especially in patients who have failed or
`are not candidates for other therapies.
`Desensitization procedures (induction of drug tolerance),
`including true immunologic desensitization (eg, to penicillin)
`and graded challenge regimens for non -IgE hypersensitivity
`reactions (eg, to trimethoprim -sulfamethoxazole), have been
`successfully used in the management of drug- induced cuta-
`neous reactions 5 -7 However, to our knowledge, no desensi-
`tization protocols for glatiramer acetate have been reported to
`date. The present study retrospectively evaluates the out-
`come, safety, and long -term utility of glatiramer acetate de-
`sensitization in a series of patients with MS who were de-
`sensitized at a single institution between January 1, 2003 and
`December 31, 2008. This study was approved by the institu-
`tional review board at the Cleveland Clinic.
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`
`CASE REPORTS
`None of the 6 patients had a history of atopy or IgE- mediated
`reactions to other medications.
`
`Patient 1
`A 31- year -old woman with MS developed urticaria on both
`arms 5 hours after her first dose of glatiramer acetate. She did
`not report associated cardiovascular, respiratory, or gastroin-
`testinal symptoms. Despite the urticaria, she continued daily
`glatiramer acetate use. Her urticarial lesions did not improve
`with antihistamine therapy (diphenhydramine and cetirizine)
`and became more generalized, involving her legs and trunk.
`She discontinued glatiramer acetate use after 10 days due to
`persisting and worsening urticaria. Within 2 days, her urti-
`caria had completely resolved. She was evaluated 1 week
`after suspending glatiramer acetate use. Examination did not
`reveal remarkable findings. Skin testing was not performed
`owing to dermatographism. The patient returned 1 week later
`for desensitization.
`
`Patient 2
`A 43- year -old man with MS developed generalized pruritus
`followed by urticaria within 30 minutes of glatiramer acetate
`administration. He had tolerated daily glatiramer acetate ther-
`apy for 2 to 3 months without adverse reaction. He sought
`emergency department management for this reaction, where
`he received epinephrine, diphenhydramine, and a nebulized
`bronchodilator. He responded well to this treatment and was
`advised to suspend glatiramer acetate use. He presented ap-
`proximately 2 months later. Skin testing was performed, and
`the patient agreed to return for desensitization.
`
`Patient 3
`A 35- year -old man with MS reported almost immediate onset
`of facial swelling, palpitations, throat constriction, and short-
`ness of breath after glatiramer acetate administration. These
`symptoms subsided spontaneously within 15 minutes, and the
`patient reported chills afterward. On another occasion, he
`reported a sensation of throat constriction along with short-
`ness of breath within 1 minute of administration of glatiramer
`acetate. These symptoms subsided within 15 minutes. The
`patient had tolerated glatiramer acetate therapy for approxi-
`mately 2 years before these episodes without adverse reac-
`tion. He was seen approximately 2 months after suspending
`glatiramer acetate therapy. Skin testing and desensitization to
`glatiramer acetate were performed.
`
`Patient 4
`A 30- year -old woman with MS tolerated glatiramer acetate
`therapy for 5 years without adverse reaction but then devel-
`oped respiratory symptoms on 3 occasions after glatiramer
`acetate administration. During one episode, she experienced
`chest tightness and difficulty breathing along with headache
`and facial flushing. Within minutes, she developed hives that
`she described as pruritic, erythematous, raised areas on her
`
`chest, neck, and upper torso. She took diphenhydramine and
`the symptoms resolved. She elected to discontinue glatiramer
`acetate use. She was seen approximately 2 months later. Skin
`testing and desensitization were performed.
`
`Patient 5
`A 32- year -old man with aggressive MS was given glatiramer
`acetate. Five weeks after initiating glatiramer acetate therapy
`he experienced injection site pruritus within an hour of med-
`ication administration followed by the development of local
`hives and swelling. There was no associated angioedema or
`urticaria distant from the site of injection and no respiratory
`or cardiovascular symptoms. Glatiramer acetate therapy was
`suspended and his symptoms resolved. The patient presented
`for skin testing and desensitization.
`
`Patient 6
`A 25- year -old woman with MS experienced large local reac-
`tions after glatiramer acetate administration. She developed
`local injection site erythema, swelling, and tenderness. These
`reactions did not involve other organ systems. Despite these
`reactions the patient continued using glatiramer acetate for
`several months. She eventually suspended use of the medi-
`cation and presented after almost a year for skin testing and
`possible desensitization to glatiramer acetate at the request of
`her neurologist.
`
`METHODS
`
`Skin Testing
`Stock suspensions (20 mg /mL) of glatiramer acetate were
`prepared. Serial dilutions were formulated at the following
`concentrations: 0.2 and 2 mg /mL. Percutaneous and intrad-
`ermal skin tests were performed. The immediate reaction
`(wheal and flare) was read at 15 minutes. A positive hista-
`mine (10 mg /mL) control and a negative saline control were
`applied in parallel with the test allergens to control for anti-
`histamine premedication and dermatographism.8 Nine healthy
`volunteers who had never been exposed to glatiramer acetate
`also underwent skin testing. During this study, it was found
`that the 2 -mg /mL concentration of glatiramer acetate pro-
`voked irritant reactions in most controls. For this reason,
`further dilutions of 0.02 and 0.002 mg /mL were made from
`the stock solution. Patients who underwent evaluation early
`in the study did not undergo skin testing with these dilutions.
`
`Subcutaneous Desensitization
`Stock suspensions of glatiramer acetate were prepared by
`dissolving the contents of the 20 -mg stock vial in sterile water
`to a concentration of 2 mg/mL. Serial dilutions were formu-
`lated using 1 mL of sterile water as a diluent in the following
`concentrations: 0.00002, 0.0002, 0.002, 0.02, and 0.2 mg /mL.
`Each patient gave informed consent for subcutaneous desen-
`sitization in a closely supervised clinical setting beginning
`with 20 ng and gradually increasing dosages every 30 min-
`utes (Table 1). No premedication was given. After close
`
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`MYLAN PHARMS. INC. EXHIBIT 1070 PAGE 2
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`

`
`Table 1. Standard Glatiramer Acetate Desensitization Protocol
`Preparation
`Timing
`Route
`Dose, mg
`
`0.00002
`0.0002
`0.002
`0.02
`0.2
`2
`4
`8
`
`1 mL vial 6
`1 mL vial 5
`1 mL vial 4
`1 mL vial 3
`1 mL vial 2
`1 mL vial 1
`0.2 mL stock vial
`0.375 mL stock vial
`
`0:00
`0:30
`1:00
`1:30
`2:00
`2:30
`3:00
`3:30a
`
`SC right abdomen
`SC left abdomen
`SC right thigh
`SC left thigh
`SC right flank
`SC left flank
`Right abdomen
`Left abdomen
`
`Abbreviation: SC, subcutaneous.
`a Observe for 30 minutes after administration of the last dose.
`
`observation for signs and symptoms of adverse reaction for
`30 minutes after the last dose, patients were discharged with
`instructions to take 20 mg of glatiramer acetate subcutane-
`ously the next morning and to continue that dose without a
`lapse of more than 48 hours between doses. If there was a
`lapse greater than 48 hours between 2 doses, the patient was
`advised that he or she would be considered resensitized and
`would have to return for another desensitization. The patients
`were provided with self -injectable epinephrine and were in-
`structed in its correct use.
`
`RESULTS
`
`Skin Testing
`Skin testing was performed in 5 of 6 patients (patient 1 was
`dermatographic) and in 9 controls not previously exposed to
`glatiramer acetate. Of the 5 patients, 3 exhibited remarkable
`wheal- and -flare reactions at 1:10 dilution (2 mg /mL), and 2
`had wheal -and -flare reactions at 1:100 dilution (0.2 mg /mL).
`One patient was tested at 1:1000 (0.02 mg /mL) and 1:10,000
`(0.002 mg /mL) and had wheal- and -flare reactions at 1:1000
`(0.02 mg /mL) only. For the controls, percutaneous testing
`with full- strength glatiramer acetate was performed. One of 9
`controls had a wheal- and -flare reaction, and further testing
`was discontinued in that individual. Intradermal testing was
`performed in the remaining 8 controls. All 8 controls had
`wheal- and -flare reactions to glatiramer acetate at 1:10 dilu-
`tion (2 mg /mL) and 6 at 1:100 dilution (0.2 mg /mL) at the
`intradermal level, suggesting that these dilutions elicited ir-
`ritant reactions. Further dilutions of 1:1000 (0.02 mg /mL) and
`1:10,000 (0.002 mg /mL) were made in an attempt to find a
`testing concentration that would not elicit irritant reactions,
`and intradermal testing was performed with these dilutions in
`5 controls. Four of 5 controls exhibited wheal - and -flare re-
`action to 1:1000 dilution (0.02 mg /mL) and 2 of 5 to 1:10,000
`dilution (0.002 mg /mL).
`
`Subcutaneous Desensitization
`Successful subcutaneous desensitization was performed in all
`6 patients. Patient 5 tolerated the desensitization procedure
`without adverse reaction. However, the following day when
`he administered glatiramer acetate, he had a recurrence of
`
`local injection site swelling and erythema. These reactions
`continued despite pretreatment with antihistamines. The pa-
`tient continued the medication therapy for approximately 14
`months after the "desensitization" but eventually suspended
`glatiramer acetate therapy due to persistent local reactions.
`to 4 underwent desensitization to glatiramer
`Patients 1
`acetate and tolerated the procedure well. There were no
`immediate or subsequent adverse reactions. These patients
`have continued daily glatiramer acetate administration, with
`the longest duration of therapy with glatiramer acetate after
`desensitization without adverse reactions of 39 months (pa-
`tient 4).
`Patient 6 underwent desensitization to glatiramer acetate as
`well. She reported symptoms of mild dizziness after 3 doses
`were administered. This resolved in less than 1 hour with 60
`mg of oral fexofenadine. The symptom of dizziness was
`interpreted as a non -IgE- mediated reaction. The desensitiza-
`tion protocol was resumed, and the patient advanced through
`the remaining doses without further adverse reactions. She
`was successfully desensitized and continued glatiramer ace-
`tate therapy for approximately 8 months. At that time, the
`patient became pregnant and suspended glatiramer acetate
`treatment. Table 2 summarizes the patient characteristics and
`their outcomes.
`
`DISCUSSION
`Adverse reactions to glatiramer acetate are common and may
`lead to suspension of treatment. We demonstrated that this
`desensitization protocol can be performed safely and can
`permit resumption of daily glatiramer acetate administration.
`The most common adverse effect of glatiramer acetate
`administration is injection site reaction, including erythema
`in 66% of patients, induration in 13 %, inflammation in 49 %,
`and pain in 73 %4 Ten percent of patients experienced im-
`mediate postinjection systemic reactions characterized by
`flushing, chest pain, palpitations, anxiety, dyspnea, throat
`constriction, and urticaria.4 The adverse effects to glatiramer
`acetate reported by patients in this study are consistent with
`reports in the literature.
`In this cohort, patients 3, 4, and possibly 2 had persistent
`systemic reactions after glatiramer acetate administration.
`These patients were successfully desensitized to glatiramer
`acetate. Patient 1 reported a systemic reaction that occurred 5
`hours after taking the first dose of glatiramer acetate, which
`is unlikely to represent an IgE- mediated reaction. Yet, he was
`successfully desensitized to glatiramer acetate. Patients 5 and
`6 had large local reactions at the injection site, and desensi-
`tization in one (patient 6) led to the resumption of glatiramer
`acetate therapy without remarkable local reactions with re-
`peated administration. Bayerl et alp reported an unsuccessful
`attempt to desensitize a patient to glatiramer acetate who had
`experienced a systemic reaction with previous glatiramer
`acetate use. To our knowledge, this is the first report of
`successful desensitization to glatiramer acetate.
`In our experience, glatiramer acetate skin testing elicited
`an irritant reaction in controls and patients. For this reason,
`
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`

`
`Result of desensitization
`
`Clinical course
`
`No recurrence of urticaria
`No recurrence of urticaria
`
`Tolerating GA
`Tolerating GA
`
`No recurrence of systemic
`symptoms
`No recurrence of systemic
`symptoms
`Recurrence of local
`reaction
`
`Tolerating GA
`
`Tolerating GA
`
`Patient stopped GA 14
`mo later due to
`persistent reactions
`Continued GA for 8
`mo, then stopped
`due to pregnancy
`
`Table 2. Clinical Characteristics and Outcomesa
`Patient
`No. /Sex/Age, y
`
`Adverse reaction
`
`Skin testing
`positive at
`
`Reactions during
`desensitization
`
`1/F/31
`2/M/43
`
`3/M/35
`
`4/F/30
`
`5/M/32
`
`Generalized cutaneous
`Generalized cutaneous
`
`Immediate -onset
`systemic
`Immediate -onset
`systemic
`Local injection site
`
`Not done
`0.2 -mg /mL irritant
`response
`0.2 -mg /mL irritant
`response
`2 -mg /mL irritant
`response
`2 -mg /mL irritant
`response
`
`None
`None
`
`None
`
`None
`
`None
`
`6/F/25
`
`Local injection site
`
`2 -mg /mL irritant
`response
`
`Mild dizziness
`
`No recurrence of local
`reaction
`
`Abbreviations: GA, glatiramer acetate; MS, multiple sclerosis.
`a Eight of 8 controls had positive skin test results at 1:10 (2 mg /mL), 6 of 8 at 1:100 (0.2 mg /mL), 4 of 5 at 1:1000 (0.02 mg /mL), and 2 of 5 at
`1:10,000 (0.002 mg /mL). This indicates that skin testing is unreliable owing to an irritant response.
`
`wheal- and -flare reaction cannot be interpreted as indicative
`of sensitization. There may be several reasons for this: (1) the
`glatiramer acetate preparation is extremely irritating to the
`skin even at very low concentrations; (2) we used intradermal
`testing, which has inherent issues with reproducibility and
`person -person variability; (3) the controls may be sensitized
`as these sequences are naturally occurring amino acids; and
`(4) the use of sterile water as a diluent for skin testing may
`have elicited an irritant reaction. To test the latter hypothesis,
`skin testing was repeated using normal saline as diluent;
`however, this was also associated with frequent irritant reac-
`tions in controls, which implies that sterile water is not the
`cause of irritant reactions (data not shown). Based on these
`findings, we cannot recommend immediate hypersensitivity
`skin testing in the evaluation and management of patients
`with adverse reactions to glatiramer acetate. Bayerl et al'
`performed percutaneous and intradermal skin testing in 5
`control patients and in 1 patient who had a systemic reaction
`after subcutaneous use of glatiramer acetate. The patient had
`wheal- and -flare reactions to full- strength glatiramer acetate
`on intradermal testing at 15 minutes and 24 hours, which was
`not observed in the 5 control subjects (data not shown). These
`results are significantly different than those of the present
`skin testing, which may be due to the person -person variabil-
`ity seen with intradermal skin testing.
`Although immediate postinjection systemic reactions clin-
`ically resemble anaphylaxis, they have an unpredictable and
`sporadic nature, and their pathogenesis is not well under-
`stood. Most patients treated with glatiramer acetate develop
`anti - glatiramer acetate IgG4 without anti - glatiramer acetate
`IgE antibodies 210 This may be explained by the immuno-
`modulatory actions of the drug. Although glatiramer acetate
`treatment induces a switch from the TH1 to the TH2 pheno-
`type, it also induces regulatory T cells that suppress TH1 and
`TH2 immune responses. That could account for the clinical
`
`efficacy and the low incidence of IgE- mediated reactions.2, ".i2
`It is also possible that because patients are taking glatiramer
`acetate daily, they are in a "desensitized" state; perhaps if
`they then miss 1 or more doses and then administer the
`medication they could provoke a systemic reaction. That
`could account for the sporadic nature of the immediate
`postinjection systemic reaction observed in glatiramer ace-
`tate- treated patients. Another possible explanation for these
`frequent systemic reactions may be a nonimmunologic ana-
`phylactic (anaphylactoid) reaction to glatiramer acetate.
`Although anaphylaxis to glatiramer acetate is rare, it has
`been reported.9"13 Rauschka et al13 investigated whether anti -
`glatiramer acetate IgE antibodies were present in 1 patient
`with anaphylaxis to glatiramer acetate and found detectable
`specific IgE levels in the serum, demonstrating that anti -
`glatiramer acetate IgE can occur in glatiramer acetate -treated
`patients.
`Each vial of glatiramer acetate injection contains 40 mg of
`mannitol. Mannitol infusion has been reported to cause ana-
`phylactoid reactions.14 Mannitol inhalation causes increased
`levels of prostaglandin D2 and leukotriene C4, consistent with
`mast cell activation.15 We did not evaluate the patients for
`mannitol hypersensitivity and cannot rule out the possibility
`that these reactions may be secondary to mannitol. The true
`mechanism of action underlying glatiramer acetate -induced
`hypersensitivity reactions requires further study.
`Glatiramer acetate administration can reduce the relapse
`rate of MS by approximately 30% after 2 years of therapy.' A
`double -blind, placebo -controlled study16 demonstrated a re-
`duction in the number of gadolinium- enhancing lesions in
`patients receiving glatiramer acetate compared with a pla-
`cebo. Glatiramer acetate may also have a favorable effect in
`preventing tissue loss at a later diseased stage." "'8 Based on
`these data, subcutaneously administered glatiramer acetate is
`one of the most widely prescribed drugs for the treatment of
`
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`

`
`relapsing- remitting MS.' Although recurrence and severity of
`reactions to glatiramer acetate are unpredictable, treating
`through "hypersensitivity reactions" or rechallenge may be
`dangerous. The need for a successful desensitization protocol
`is highlighted by the fact that cutaneous reactions to glati-
`ramer acetate occur in up to 66% and immediate postinjection
`systemic reactions in up to 10% of patients with MS.
`Subcutaneous desensitization to glatiramer acetate using
`this protocol seems to be safe. We observed no systemic
`reactions during desensitization or during follow -up of these
`patients as judged by the ability to tolerate long -term glati-
`ramer acetate therapy after desensitization. The procedure
`was successful in all 5 patients with systemic reactions and in
`1 of 2 patients with large local reactions. The procedure was
`successful in patients with reactions suggestive of IgE -medi-
`ated reactions and in patients with reactions that were clearly
`not IgE mediated (patients 1 and 6). Experience with more
`patients is required to confirm the efficacy of this subcuta-
`neous desensitization protocol. We conclude that subcutane-
`ous desensitization is an important option for patients devel-
`oping cutaneous or systemic reactions to glatiramer acetate,
`which may permit patients with MS who have achieved
`benefit with glatiramer acetate therapy to safely resume reg-
`ular glatiramer acetate treatment.
`
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`Requests for reprints should be addressed to:
`David M. Lang, MD
`Respiratory Institute
`Allergy /Immunology Section
`Cleveland Clinic
`9500 Euclid Ave, C -22
`Cleveland, OH 44195
`E -mail: langd @ cqf. org
`
`VOLUME 104, APRIL, 2010
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`325
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`MYLAN PHARMS. INC. EXHIBIT 1070 PAGE 5