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.
`
`Name of the medicinal product
`Fumaderm Initial
`Fumaderm
`
`Qualitative and quantitative composition
`The active ingredients of Fumaderm Initial and Fumaderm are:
`Dimethyl fumarale;
`Ethyl hydrogen fumarate, calcium salt;
`Ethyl hydrogen fumarate, magnesium salt;
`Ethyl hydrogen fumarate, zinc salt.
`
`1 gastro—resistant tablet contains:
`
`Dimeth I fumarate
`
`Calcium salt
`
`67 m
`
`87 m
`
`Ma-nesium salt
`
`5 m-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Zinc salt
`
`
`3 mo
`
`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 vulgan’s), in cases where
`previous, externally applied, stand~alone treatments have failed. Prior to administration, patient
`toierability must firstly be reinforced by treatment with Fumaderm Initial (q.v.).
`
`4.2
`
`Posology and method of administration
`Fumaderm Initial:
`
`Unless othenrvise 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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`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 ‘l
`gastro—resistant Fumaderm tablet once daily (evenings).
`
`Dosage
`
`
`
`mm_ Lunchtimes
`
`venin-s
`
`
`
`A—Lm
`
`
`
`Fumaderm:
`
`Unless otherwise prescribed, dosage instructions 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 to the following
`chart:
`
`
`
`
`1
`2
`3
`4
`5
`6
`
`Mornins
`-
`1
`1
`1
`2
`2
`
`Lunchtimes
`
`-
`1
`1
`1
`2
`
`Evenin-s
`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 (1V2 - 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
`
`F umaderm Initial and Fumaderm are contraindicated in the following cases:
`— Known hypersensitivity to the active ingredients (dimethyl fumarate; ethyl hydrogen 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 vulgaris, e.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 psoriasis— although isolated case reports
`would seem to indicate some degree of therapeutic efficacy;
`In patients below 18 years of age;
`
`—
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`— During pregnancy and lactation.
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`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 treatment initiation 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 levels — particularly if values should fall below
`3000/mm3 — or if there are any other pathologic changes in 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 treatment initiation 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. ?herapy 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 lnitiall 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 fu maric acid derivatives (eg. in the form of ointments 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 teratogenic effect,
`Although, on the basis of animal experiments,
`Fumaderm Initial and Fumaderm should not be used during either pregnancy or lactation, as there is a
`lack of clinical experience regarding use during human pregnancy, and it is not known whether their active
`substances are excreted in human milk.
`
`4.? 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)
`
`Common:
`(> 1! 100 of patients treated)
`
`
`
`Uncommon:
`
`Rare:
`
`(1/ 1,000 of patients treated)
`
`(1/ 10,000 of patients treated)
`
`
`
`Very rare:
`(5 1/ 10,000 patients; including isolated cases)
`
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`Undesirable effects and counter-measures
`
`Skin and subcutaneous disorders:
`
`Vent 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:
`
`Veg; common:
`— Diarrhoea
`
`Common:
`— Feelings of bloatedness
`— Upper abdominal cramps
`— Flatulence
`
`Uncommon:
`— Nausea
`
`These undesirable effects are very common at initiation 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 blood 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 lymphopenia (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
`
`Veg rare:
`— Persistent eosinophilia
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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 changes are reversible upon discontinuation of therapy.
`
`Veg 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 (of.
`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:
`
`Veg 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 treatment is indicated. There is no 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:
`Fumaric acid esters influence the regulatory site of succinate dehydrogenase within the citric acid cycle.
`Dimethyl fumarate, monomethyl fumarate (the main metabolite of dimethyl 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—belper 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 hypotensive 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 (Le. reduction in blood pressure, increased saluresis
`and diuresis) were not reproduced at therapeutic dosage regimens within humans.
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`5.2 Pharmacoklnetic properties
`Pharmacokinetic studies have been performed both in vitro and in viva. 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 dimethyl fumarate to monomethyl 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 down 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 levels remained constant throughout all 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 mgll) is reached after 5 — 6 hours. The mean
`in vivo lag-time of 313 minutes (5 — 6 hours) confirms the efficacy of the tablets 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).
`
`Chronic 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 lnitial/
`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 pathologicallanatomical changes (in rats: pachyderma of the
`stomach, 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 dogs over a 52-week period, which induced dose—dependent renal 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 to 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 lactation are lacking. It is not known whether the 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 mutagenlc risk for humans can be ruled out. This applies for
`the active ingredient blend, as well as its individual compounds. Carcinogenicity studies 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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`6.1 List of excipients
`Fumaderm lnitial:
`
`acid-methyl
`171), methacrylic
`{E
`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), macrogol 6000,
`slmethlcone, povidon, dibutyl phthalate, microcrystalline cellulose, colloidal anhydrous silica.
`
`6.2 lncompatibilitées
`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:
`
`4O 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 T250130I90 polymer film-aluminium foil).
`
`Fumaderm:
`
`70 gastro—resistant tablets [E
`Each pack contains 7 blister strips, each strip containing 10 gastro—resistant tablets:
`The film-coated tablets are packed in blister strips (alfoil T250130l90 polymer film-aluminium foil).
`
`100 gastro-resistant tablets
`Each pack contains 10 blister strips, each strip containing 10 gastro-resistant tablets:
`The film-coated tablets are packed in blister strips (alfoil T250130190 polymer film-aluminium foil).
`
`200 gastro—resistant tablets*
`Each pack contains 20 blister strips, each strip containing 10 gastro-resistant tablets:
`The film-coated tablets are packed in blister strips (alfoil T250l301’90 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 packed in blister strips (alfoil T2501301‘90 polymer film—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
`FUMEDICA Arzneimittel GmbH
`Industriestralse 40
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`D-44628 Heme
`
`Germany
`Tel.: 0049 (0) 23231 1496 0
`Fax: 0049 (0) 2323! 1496 20
`
`Co-distribulor:
`HERMAL KURT HERRMANN GmbH & Co OHG
`Scholtzstralie 3
`13-21465 Reinbek
`
`Germany
`Tel.: 0049 (0) 40! 727 04 0
`Fax: 0049 (0) 40/ 722 92 96
`
`Under licence from:
`Fumapharm AG Schweiz
`CH-6006 Lucerne
`Switzerland
`
`8. Marketing authorisation number/s
`Fumaderm Initial. gastro—resistant tablets:
`275810000
`
`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
`
`1 1. Prescription status] Availability
`Available on prescription only
`Please send all inquiries to:
`BPI Service Gran
`Fachlnfo-Service
`PO Box 12 55
`D-88322 Aulendorf
`
`Germany
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