EXHIBIT A
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`Sawai (IPR2019-00789), Ex. 1020, p. 001
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`Sawai (IPR2019-00789), Ex. 1020, p. 001
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`

`

`Summary of Product Characteristics
`
`Fumaderm® Initial
`Fumaderm®
`
`1.
`
`2,
`
`Nameof the medicinal product
`Fumaderm Initial
`Fumaderm
`
`Qualitative and quantitative composition
`The active ingredients of Fumaderm initial and Fumaderm are:
`Dimethyl fumarate;
`Ethyl hydrogen fumarate, calcium salt;
`Ethyl hydrogen fumarate, magnesium salt;
`Ethyl hydrogen fumarate, zinc salt.
`
`1 gastro-resistant tablet contains:
`
`
`
`
`
`67 mg
`
`5 mg
`
`3mg
`
`87 mg
`
`gi
`
`3mg
`
`
`
`
`
`Calcium salt
`
`Magnesium salt
`
`Zine salt
`
`3.
`
`4,
`
`4,1
`
`For excipients, see section 6.1
`
`Pharmaceutical Form
`Gastro-resistant tablet for oral use.
`
`Clinical Particulars
`
`Therapeutic Indications
`Fumaderm Initial.
`Indicated to improve patient tolerability to Fumaderm therapy during the start-up phase.
`
`Fumaderm:.
`Indicated for the treatment of severe forms of plaque psoriasis (Psoriasis vulgaris), in cases where
`previous, externally applied, stand-alone treatments have failed. Prior to administration, patient
`tolerability mustfirstly be reinforced by treatment with Fumaderm Initial (q.v.).
`
`4.2
`
`Posology and method of administration
`Fumaderm Initial:
`Unless otherwise prescribed, dosage instructions are as follows:
`
`In reaching the optimal efficacy and tolerability profile, dose escalation should be gradual. During
`the first week of treatment,
`1 gastro-resistant Fumaderm Initial tablet should be taken once daily
`(evenings). During Week 2, this daily dose should be increased to 2 gastro-resistant Fumaderm
`Initial tablets (1 x mornings and 1 x evenings}. During Week 3 (daily dose = 3 gastro-resistant
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`Sawai (IPR2019-00789), Ex. 1020, p. 002
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`tablets has finished,
`tablets), as soon as the course of Fumaderm Initial
`Fumaderm Initial
`treatment should be immediately switched over to Fumaderm,viz. at an initial daily dose of 1
`gastro-resistant Fumaderm tablet once daily (evenings).
`
`
`
`
`
`
`
`[Mornings—S—~—~=*éidsCLuintchtimes=C*dTEvenings=
`1
`-
`1
`
`2
`1
`1
`
`3
`1
`1
`
`
`
`
`
`
`
`Fumaderm:.
`Unless otherwise prescribed, dosageinstructions are as follows:
`Following pre-treatment with Fumaderm Initial to increase tolerability, treatment should be switched over
`to Fumaderm during the third week of treatment.
`During the first week of treatment with Fumaderm, 1 gastro-resistant Fumaderm tablet should be taken
`once daily (evenings). Depending on individual
`tolerability,
`this daily dosage should be increased in
`weekly increments (i.e. by one gastro-resistant Fumaderm tablet per week), according ta the following
`chart:
`
`1
`2
`3
`4
`5
`6
`
`
`
`
`
`-
`4
`4
`1
`2
`2
`
`Lunchtimes
`-
`
`Ev
`1
`1
`1
`2
`2
`2
`
`
`
`
`
`
`The maximum daily dosage of 3 x 2 gastro-resistant Fumaderm tablets must not be exceeded. However,
`in most cases, administration of this maximum daily dosage is not needed. Clinical experience has shown
`that the initial therapeutic effects are noticed within 4 —6 weeks of treatment.
`When skin reactions subside, daily dosage should be reduced gradually until the individual maintenance
`dose is reached. Fumaderm gastro-resistant tablets should be swallowed whole (not chewed) with plenty
`of liquid during or immediately after a meal. Patients should be advised to drink sufficient amounts of
`water during the day (1% - 2 litres). Duration of treatment is left up to the discretion of the treating
`physician. Adequate experience gained during clinical
`trials would suggest a treatment period of four
`months. However, clinical experience exists of treatment periods of up to 36 months, recorded within the
`framework of post-marketing observational studies.
`
`4.3 Contraindications
`Fumaderm Initial and Fumaderm are contraindicated in the following cases:
`— Known hypersensitivity to the active ingredients (dimethyl fumarate; ethyl hydragen fumarate
`calcium/ magnesium and/or zinc salt) or any of the excipients used in Fumaderm Initial/
`Fumaderm;
`Severe gastrointestinal disease, such as gastric and/or duodenal ulcers;
`—
`Severe hepatic and renal disease:
`-
`— Due to the therapeutic risk involved (risk/ benefit ratio), mild cases of Psoriasis vuigaris, ¢.g.
`circumscribed plaque psoriasis or chronic stationary plaque psoriasis covering less than 10% of
`total body surface;
`— Due to insufficient clinical experience, cases of pustular pscriasis— although isolated case reports
`would seem to indicate some degree of therapeutic efficacy;
`Inpatients below 18 years of age:
`
`—
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`Sawai (IPR2019-00789), Ex. 1020, p. 003
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`- During pregnancy and lactation.
`
`4.4 Special warnings and special precautions for use
`Prior to initiation of treatment with Fumaderm Initial and Fumaderm, a full blood count (including a
`differential count and platelets) should be performed. In the presence of values outside the normal range,
`treatment with Fumaderm Initial and Fumaderm must not be instituted. During the course of treatment, full
`blood counts (leukocyte count and differential count) must be monitored on a regular basis. Tests should
`be performed no earlier than 14 days following treatmentinitiation and within the first three months of
`therapy. If results from these tests reveal no anomalies, a full blood count (performed on a monthly basis
`thereafter) is sufficient. Treatment with Fumaderm Initial or Fumaderm should be suspended immediately
`in the presence of a significant reduction in leukocyte !evels — particularly if values should fall below
`3000/mm3 — orif there are any other pathologic changesin the blood count. In such events, blood count
`levels should be monitored until normalisation is achieved. Similarly, prior to and during treatment, the
`following parameters should be tested (no earlier than 14 days following treatmentinitiation and within the
`first four weeks; and every four weeks thereafter) to identify any possible adverse effects on liver and
`kidney function: SGOT (ASAT) and SGPT (ASAT) activity; Gamma GT; AP;
`serum creatinine
`concentrations; proteinuria; urinary sediment. Furthermore, caution should be exercised in the presence of
`haematological disorders. Therapy should be discontinued in the case of increased creatinine levels
`above the normal range.
`
`4.5 Interaction with other medicinal products and other forms of interaction
`Whilst receiving Fumaderm Initial/ Fumaderm therapy, concomitant use of the following is not permitted:
`methotrexate, retinoids, psoralens, cyclosporine, immunosuppressants, cytostatics and drugs known to
`impair renal function. During treatment with Fumaderm Initial’ Fumaderm, concomitant topical application
`of fumaric acid derivatives (e.g. in the form of cintments and/or baths) should be avoided, as the additional
`uptake of these derivatives, found in certain ointments and bath formulations, may lead to an overdose as
`a result of exceeding the maximal tolerable dose.
`
`4.6 Pregnancy and lactation
`there are no indications of any teraiogenic effect,
`Although, on the basis of animal experiments,
`Fumaderm Initial and Fumaderm shouid not be used during either pregnancy or lactation, as there is a
`iack of clinical experience regarding use during human pregnancy, andit is not Known whethertheir active
`substances are excreted in human milk.
`
`4.7 Effects on ability to drive and use machines
`When used at recommended doses, it can be expected that Fumaderm Initial and Fumaderm have no
`effect on the ability to drive or operate machinery.
`
`4.8 Undesirable effects
`Undesirable effects have been evaluated in accordance with the following frequency convention:
`
`Very common:
`(> 1/10 of patients treated}
`
`Uncommon:
`(1/ 1,000 of patients treated)
`
`rare:
`Very
`(Ss 1/ 10,000 patients; including isolated cases)
`
`
`
`
`
`Common:
`(> 1/ 100 of patients treated)
`
`Rare:
`(1/ 10,000 of patients treated)
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`Sawai (IPR2019-00789), Ex. 1020, p. 004
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`Undesirable effects and counter-measures
`
`Skin and subcutaneous disorders:
`Very common:
`— Facial redness and hot flushes
`These disorders occur very frequently at initiation of therapy and usually subside during the course of
`treatment. However, severe manifestations of this kind may necessitate the discontinuation of treatment
`with either product.
`
`Rare:
`— Allergic skin reactions
`These disorders are reversible upon discontinuation of treatment.
`
`Gastrointestinal disorders:
`Very common:
`— Diarrhoea
`
`Common:
`— Feelings of bloatedness
`— Upper abdominal cramps
`— Flatulence
`
`Uncommon:
`— Nausea
`
`These undesirable effects are very commonatinitiation of therapy and usually subside during the course
`of treatment.
`In most cases, reduced dosage is sufficient to alleviate these disorders. However, should
`these effects persist, the treating physician should consider the possibility of discontinuing therapy.
`
`Nervous system disorders.
`Uncommon:
`— Tiredness
`— Dizziness
`— Headaches
`In most cases, reduced dosage is
`These side effects usually subside during the course of treatment.
`sufficient to alleviate these disorders. However, should these effects persist, the treating physician should
`consider the possibility of discontinuing therapy.
`
`Blood and lymphatic system disorders:
`Changes in blocd count levels, such as leuko/ lymphopenia and varying degrees of eosinophilia, have
`been reported (cf. section 4.4: “Special warnings and special precautions for use”):
`
`Very common:
`— mild forms of lymphopenia (approx. 50% of patients)
`— mild leukopenia (approx. 11% of patients)
`
`Common:
`— More severe forms of lymphepenia (approx. 3% of patients)
`Signs of lymphopenia and leukopenia may regress. However, they may also repeatedly reoccur during
`treatment or even progress over the longer term.
`
`Common:
`— Transient eosinophilia
`
`Very rare:
`— Persistent eosinophilia
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`Sawai (IPR2019-00789), Ex. 1020, p. 005
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`There are no indications to suggest that these changes in blood count values might lead to opportunistic
`infections. The above-mentioned blood count changesare reversible upon discontinuation of therapy.
`
`Very rare:
`— Acute lymphatic leukaemia (ALL)
`Isolated case:
`— Irreversible pancytopenia
`
`Renal and urinary disorders:
`Uncommon:
`— Proteinuria
`— Increased serum creatinine concentrations
`
`Therapy should be discontinued in the case of increased creatinine levels above the normal range (cf.
`section 4.4: “Special warnings and special precautions for use”).
`
`Hepatobiliary disorders:
`Uncommon:
`— Increased liver values (SGOT [ASAT], SGPT [ALAT], Gamma GT)
`
`Other undesirable effects.
`Very rare:
`— Occurrence of non-specific bone pains and increased alkaline phosphatase accompanied by decreased
`inorganic phosphate levels. This phenomenon may be linked to bone disease. These disorders and
`abnormal levels are reversible upon discontinuation of therapy.
`
`4.9 Overdose
`in addition to general measures to eliminate toxins and reduce gastrointestinal
`In cases of overdose,
`absorption, appropriate symptomatic treatmentis indicated. There is nc Known specific antidote.
`
`5, Pharmacological properties
`
`5.1 Pharmacodynamic properties
`Fumaderm Initial and FUMADERM contain fumaric acid esters.
`Pharmacotherapeutic group: systemic anti-psoriasis products.
`ATC code: DOSBX51
`
`Preclinical studies are lacking due to the absence of suitable animal models. The current state of
`knowledge on the mechanism of action for fumaric acid esters is based on the following scientific results:
`Fumarie acid esters influence the regulatory site of succinate cehydrogenase within thecitric acid cycle.
`Dimethyl fumarate, monomethyl fumarate (the main metabolite of dimethy! fumarate) and monoethyl
`fumarate inhibit the proliferation of ceratinocytes, possibly due to a transient increase in intracellular Ca2+
`concentrations. Therapy with Fumaderm Initial’ Fumaderm reduces intraepidermal infiltration of the skin
`with granulocytes and t-helper cells, bringing about a reduction in acanthosis and hyperkeratosis.
`Monomethyl! fumarate is known to affect the cytokine secretion pattern of T-helper cells, which results in
`increased secretion of the anti-inflammatory cytokines IL 4, IL 5 and IL10.
`
`In pharmacological safety studies involving Fumaderm Initial and Fumaderm (blend of active ingredients)
`a hypctensive effect was observed at a high doses in narcotised dogs.
`In one acute study on rats,
`increased saluresis was observed, whilst in reproductive toxicological studies, increased diuresis was
`reported. However, in clinical studies, these findings (i.e. reduction in blood pressure, increased saluresis
`and diuresis) were not reproduced at therapeutic dosage regimens within humans.
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`Sawai (IPR2019-00789), Ex. 1020, p. 006
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`5.2 Pharmacokinetic properties
`Pharmacokinetic studies have been performed both /n vitro and in vivo. Studies on rats and dogs reveal
`that, following oral administration of the Fumaderm active ingredient blend,
`individual substances were
`almost completely absorbed (approx. 30 minutes — 2 hours).
`It has been shown that,
`in the intestines,
`hydrolysation of dimethy! fumarate to monomethy| fumarate is very rapid. Peak serum levels were reached
`15 mins and 1 h respectively after administration. Studies on rats were performed after oral administration,
`using labelled dimethyl fumarate. Results from these studies clearly demonstrate that excretion mainly
`occurs via the respiratory tract, with only relatively small amounts being excreted via the stools or urine.
`Furthermore, metabolisation studies involving human serum (in vitro) have also revealed that dimethyl
`fumarate is rapidly yet completely hydrolysed to methyl hydrogen fumarate (with a half-life of 11.6
`minutes). Conversely, the processes involved in breaking cown methyl hydrogen fumarate in the serum
`are very slow (half-life = approx. 36 hours). Both dimethyl fumarate and fumaric acid have been shown not
`to be protein-bound. On the other hand, protein binding for methyl hydrogen fumarate and ethyl hydrogen
`fumarate stands at around 50% and 60%respectively.
`
`During in vivo tests, it was not possible to detect any increase in fumaric acid (metabolite). Fumaric acid
`concentration leveis remained constant throughoutall the tests performed.
`In human subject studies,
`it was revealed that dimethyl fumarate - unlike its main metabolite methyl
`hydrogen fumarate - is not detectable in the blood, which can be attributed to its rapid hydrolysis. The
`peak serum concentration of methyl hydrogen fumarate (2.4 mg/l) is reached after 5 — 6 hours. The mean
`in vivo lag-time of 313 minutes (5 — 6 hours) confirms the efficacy of the tablet’s gastro-resistant
`properties. The mean elimination half-life is around 80 minutes.
`
`5.3 Preclinical safety data
`Acute toxicity studies have revealed that the compounds used in Fumaderm Initial/ Fumaderm gastro-
`resistant tablets are more toxic on their own than when combined (LTD, LD50).
`
`Chronie toxicity studies on rats and dogs, involving oral administration of the product, have yielded the
`following results:
`-In rats, within the first few weeks of treatment, repeat-dose oral administration of Fumaderm Initial/
`Fumaderm induced leukocytosis and lymphopenia, as well as increased liver weight.
`At toxic dose levels, the main effect observed was gastric damage, which manifested itself merely as
`clinical signs (in dogs: vomiting) or as pathologicalfanatomical changes (in rats: pachyderma of the
`stemach, hyperplasia and hyperkeratosis of the cutaneous rumen mucosa, which in some cases
`developed into papillomas and carcinomas). In all probability, these effects were as a result of the acidity
`of the product's active ingredients. In assessing this phenomenon, it should be borne in mind that human
`therapeutic use of Fumaderm Initial/ Fumaderm involves tablets with a gastro-resistant coating, which
`should prevent
`similar damage from occurring in humans. Moreover,
`fumaric acid esters were
`administered to rats and dags over a 52-week period, which induced dose-dependentrenal toxicity in both
`species. This toxicity manifested itself in increased serum urea values and pathomorphological changes.
`Furthermore, in male rats exposed to levels 10 times higher than the maximum allowed in human clinical
`use, benign Leydig cell
`tumours appeared. After a 26-week treatment period, no renal or testicular
`changes were observed. Studies on rats and rabbits, exposed to doses approaching levels causing
`maternal toxicity, yielded no evidence of any teratogenic effect.
`In fact, embryo-foetal toxicity (growth
`retardation, mortality) was only observed at doses known te cause maternal toxicity. In one reproduction
`study on rats, there was no evidence to indicate any effect on fertility. Human data on use of the product
`during pregnancy and ltactation are lacking. It is not known whetherthe individual compounds making up
`this blend of active ingredients are excreted in human milk. However, on the basis of results obtained from
`in vitro and in vivo mutagenicity studies, any mutagenic risk for humans can be ruled out. This applies for
`the active ingredient blend, as well as its individual compounds. Carcinogenicity stucies are lacking. No
`effect on the immune system could be observed during subacute and chronic studies on systemic use of
`fumaric acid esters (active ingredient blend). However, targeted sensitisation studies on guinea pigs
`revealed that fumaric acid esters (active ingredient blend) and monoethyl fumarate have a sensitising
`effect, following dermal application.
`
`6. Pharmaceutical particulars
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`Sawai (IPR2019-00789), Ex. 1020, p. 007
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`Sawai (IPR2019-00789), Ex. 1020, p. 007
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`6.1 List of excipients
`Fumaderm initial:
`acid-methyl
`(E 171), methacrylic
`pigments
`talc, magnesium stearate,
`sodium,
`Croscarmellose
`(1:1), methacrylic acid-ethyl acrylate copolymer
`(1:1), macrogol 6000,
`methacrylate copolymer
`simethicone, povidon, dibutyl phthalate, microcrystalline cellulose, colloidal anhydrous silica.
`
`Fumaderm:
`Croscarmellose sodium, talc, magnesium stearate, pigments E 171 and E 132), methacrylic acid-methyl
`methacrylate copolymer
`(1:1), methacrylic acid-ethyl
`acrylate copolymer
`(1:1), macrogel 6000,
`simethicone, povidon, dibutyl phthalate, microcrystalline cellulose, colicidal anhydrous silica.
`
`6.2 Incompatibilities
`Not applicable
`
`6.3 Shelf life
`3 years
`
`6.4 Special precautions for storage
`No special! requirements for storage
`
`6.5 Nature and contents of container
`Fumaderm initial:
`40 gastro-resistant tablets
`Each pack contains 4 blister strips, each strip containing 10 gastro-resistant tablets:
`The film-coated tablets are packed in blister strips (alfoil T250/30/90 polymerfilm-aluminium foil).
`
`Fumaderm:
`70 gastro-resistanttablets[NJ
`Each pack contains 7 blister strips, each strip containing 10 gastro-resistant tablets:
`The film-coated tablets are packed in blister strips (alfoil T250/30/80 polymerfilm-aluminium foil).
`
`100 gastro-resistant tablets
`Each pack contains 10 blister strips, each strip containing 10 gastro-resistant tablets:
`Thefilm-coated tablets are packed in blister strips (alfoil T250/30/90 polymerfilm-aluminium foil.
`
`200 gastro-resistant tablets*
`Each pack contains 20 blister strips, each strip containing 10 gastro-resistant tablets:
`The film-coated tablets are packedin blister strips (alfoil T250/30/90 polymer film-aluminium foil).
`
`200 gastro-resistant tablets*
`Hospital pack size
`Each pack contains 20 blister strips, each strip containing 10 gastro-resistant tablets:
`The film-coated tablets are packedin blister strips (alfoil T250/30/90 polymerfilm-aluminium foil).
`
`*These package sizes are currently not being marketed.
`
`6.6 Instructions for use, handling and disposal
`No special requirements
`
`7. Marketing authorisation holder
`FUMEDICAArzneimittel GmbH
`IndustriestraBe 40
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`Sawai (IPR2019-00789), Ex. 1020, p. 008
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`Sawai (IPR2019-00789), Ex. 1020, p. 008
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`

`

`D-44628 Herne
`Germany
`Tel.: 0049 (0) 2323/ 1496 0
`Fax: 0049 (0) 2323/ 1496 20
`
`Co-distributor:
`HERMAL KURT HERRMANN GmbH & Co OHG
`Scholtzstrake 3
`D-21465 Reinbek
`Germany
`Tel.; 0049 (0} 40/ 727 046
`Fax: 0049 (0) 40/ 722 92 96
`
`Underlicence from:
`Fumapharm AG Schweiz
`CH-6006 Lucerne
`Switzerland
`
`§. Marketing authorisation number/s
`Fumaderm Initial, gastro-resistant tablets:
`27561.00.00
`
`Fumaderm, gastro-resistant tablets:
`27561.01.00
`
`9. Date of first authorisation/ renewal of the authorisation
`Date of authorisation for Fumaderm Initial/ Fumaderm:
`09. 08. 1994
`
`10. Date of revision of the text
`April 2005
`
`11. Prescription status/ Availability
`Available on prescription only
`Please send ail inquiries to:
`BPI Service GmbH
`Fachinfo-Service
`PO Box 12 55
`D-88322 Aulendort
`Germany
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`Sawai (IPR2019-00789), Ex. 1020, p. 009
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`Sawai (IPR2019-00789), Ex. 1020, p. 009
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