HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`Cystadane safely and effectively. See full prescribing information for
`Cystadane.
`
`Cystadane (betaine anhydrous for oral solution) powder
`Initial U.S. Approval: 1996
`
`-INDICATIONS AND USAGE
`Cystadaaae is a methylating agent indicated for the treatment of
`homocystinuria to decrease elevated homocysteine blood levels. Included
`within the category of homocystinuria are (1):
`¯ Cystathionine beta-synthase (CBS) deficiency
`¯
`5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
`¯ Cobalamin cofactor metabolism (cbl) defect
`
`............................... CONTRAINDICATIONS
`¯
`None (4)
`
`-WARNINGS AND PRECAUTIONS-
`Hypermethioninemia: Cystadane may worsen elevated plasma
`methionine concentrations in patients with CBS deficiency. Cerebral
`edema has been reported in patients receiving Cystadane. (5.1)
`Monitoring: Monitor plasma methionine concentrations in patients with
`CBS deficiency. Keep plasma methionine concentrations below- 1,000
`pxnol/L through dietaxy medication and, if necessary, a reduction of
`Cystadane dose. (5.1)
`
`¯ ADVERSE REACTIONS
`Most common adverse reactions (incidence > 2%) were nausea and
`gastrointestinal distress, based on physician survey.
`
`¯
`
`¯
`
`DOSAGE AND ADMINISTRATION
`Usual dose in adult aaad pediatric patients is 6 grams per day,
`administered orally in divided doses of 3 grams two times a day. (2)
`In children less than 3 years of age, may initiate dosing at 100
`mg/kg/day, divided in twice daily doses, and then increased weekly by
`50 mg/kg increments. (2)
`Dose can be gradually increased until plasma total homocysteine is
`undetectable or present only in small aanounts. (2)
`¯ Monitor patient response by plasma homocysteine levels. (2)
`¯
`Prescribed amount of Cystadane should be measured with the measuring
`scoop provided and then dissolved in 4 to 6 ounces of water, juice, milk,
`or formula, or mixed with food for immediate ingestion. (2)
`
`¯
`
`DOSAGE FORMS AND STRENGTHS
`Powder for oral solution available in bottles containing 180 grams ofbetaine
`anhydrous. (3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`
`INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosage
`2.2 Administration
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hypermethioninemia
`
`6 ADVERSE REACTIONS
`
`6.1 Adverse Reactions in Clinical Studies
`6.2 Postmarketing Experience
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnaaacy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`To report SUSPECTED ADVERSE REACTIONS, contact Rare Disease
`Therapeutics at 1-615-399-0700, or FDA at 1-800-FDA-1088 or
`www.f da. go v/medwateh.
`
`¯
`
`¯
`
`¯
`
`USE IN SPECIFIC POPULATIONS
`Pregnancy: Animal reproduction studies have not been conducted with
`Cystadane. Use onlyifclearly needed. (8.1)
`Nursing women: It is not known whether Cystadaaae is excreted in
`human milk. Use only if clearly needed.(8.3)
`Pediatrics: Pediatric patients ranging in age from 24 days to 17 years
`have been treated with Cystadane. Children younger than 3 years of age
`may benefit from dose titration.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: April 2010
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 Storage
`
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Dosing and Administration
`
`* Sections or subsections omitted from the full prescribing information are not
`listed.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1097-0001
`
`

`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`Cystadaa~e® (betaine anhydrous for oral solution) is indicated for the treatment of homocystinuria to decrease elevated homocysteine blood levels. Included within
`the category of homocystinuria are:
`¯
`Cystathionine beta-synthase (CBS) deficiency
`¯
`5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
`¯
`Cobalamin cofactor metabolism (cbl) defect
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosage
`The usual dosage in adult and pediatric patients is 6 grams per day administered orally in divided doses of 3 graans twice daily. In pediatric patients less than
`3 years of age, dosage may be started at 100 mg/kg/day divided in twice daily doses, and then increased weekly by 50 mg/kg increments.
`
`Therapy with Cystadaaae should be directed by physicians knowledgeable in the management of patients with homocystinuria. Patient response to Cystadane can be
`monitored by homocysteine plasma levels. Dosage in all patients can be gradually increased until plasma total homocysteine is undetectable or present only in small
`amounts. Response (by homocysteine plasma levels) usually occurs within several days and steady state within a month. Plasma methionine concentrations should be
`monitored in patients with CBS deficiency [See Warnings and Precautions (15.2)].
`
`Dosages of up to 20 grams per day have been necessary to control homocysteine levels in some patients. However, one pharmacokinetic and pharmacodynamic in
`vitro simulation study indicated minimal benefit from exceeding a twice-daily dosing schedule and a 150 mg/kg/day dosage for Cystadaaae.
`
`2.2 Administration
`
`The prescribed amount of Cystadane should be measured with the measuring scoop provided (one level 1.7 mL scoop is equal to 1 gram ofbetaine
`anhydrous powder) aaad then dissolved in 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula, or mixed with food for immediate ingestion.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Cystadane is a white, granular, hygroscopic powder for oral solution available in bottles containing 180 grams ofbetaine anhydrous.
`
`4 CONTRAINDICATIONS
`
`None.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Hypermethioninemia in Patients with CBS Deficiency
`Patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency may also have elevated plasma methionine concentrations. Treatment with
`Cystadame may further increase methionine concentrations due to the remethylation of homocysteine to methionine. Cerebral edema has been reported in patients with
`hypermethioninemia, including patients treated with Cystadane. Plasma methionine concentrations should be monitored in patients with CBS deficiency. Plasma
`methionine concentrations should be kept below 1,000 gmol/L through dietary modification amd, if necessary, a reduction of Cystadane dose.
`
`ADVERSE REACTIONS
`6.1 Adverse Reactions in Clinical Studies
`The most serious adverse reaction reported with Cystadane treatment is the development of hypermethioninemia and cerebral edema in patients with CBS
`Deficiency [see Warnings and Precautions (5. l)].
`
`The assessment of clinical adverse reactions is based on a survey study of 41 physicians, who treated a total of 111 homocystinuria patients with Cystadaaae.
`Adverse reactions were retrospectively recalled and were not collected systematically in this open-label, uncontrolled, physician survey. Thus, this list may not
`encompass all types of potential adverse reactions, reliably estimate their frequency, or establish a causal relationship to drag exposure. The following adverse
`reactions were reported (Table 1):
`
`Table 1: Number of Patients with Adverse Reactions to Cystadane by Physician Survey
`
`Adverse Reactions
`Nausea
`Gastrointestinal distress
`Diarrhea
`"Bad taste"
`"Caused odor"
`Questionable psychological changes
`"Aspirated the powder"
`
`6.2 Postmarketing Experience
`
`Number of Patients
`2
`2
`1
`1
`1
`1
`1
`
`The following adverse reactions have been identified during post approval use of Cystadane. Because these reactions are reported voluntarily from a population
`of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drag exposure.
`
`In postmarketing experience with Cystadane, severe cerebral edema and hypermethioninemia have been reported within 2 weeks to 6 months of starting betaine
`therapy, with complete recovery after discontinuation of Cystadane. All patients who developed cerebral edema had homocystinuria due to CBS deficiency and had
`severe elevation in plasma methionine levels (range 1,000 to 3,000 gM). As cerebral edema has also been reported in patients with hypermethioninemia, secondary
`hypermethioninemia due to betaine therapy has been postulated as a possible mechanism of action.
`
`The following adverse reactions have been reported in patients during postmarketing use of Cystadane: anorexia, agitation, depression, irritability, personality
`disorder, sleep disturbed, dental disorders, diarrhea, glossitis, nausea, stomach discomfort, vomiting, hair loss, hives, skin odor abnormalities, and urinary incontinence.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1097-0002
`
`

`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy Category C: Animal reproduction studies have not been conducted with Cystadane. It is also not known whether Cystadane can cause fetal harm when
`administered to a pregnant woman or can affect reproduction capacity. Cystadaaae should be given to a pregnant womaaa only if clearly needed.
`
`8.3 Nursing Mothers
`
`It is not known whether Cystadame is excreted in humam milk. Use only if clearly needed.
`
`8.4 Pediatric Use
`
`The majority of case studies of homocystinuria patients treated with Cystadane have been pediatric patients, including patients ranging in age from 24 days to 17
`years [see Clinical Studies’ (14)]. Children younger than 3 years of age may benefit from dose titration [see Dosage and Administration (2)].
`
`10 OVERDOSAGE
`
`In an acute toxicology study in rats, death occurred frequently at doses equal to or greater than 10 g/kg.
`
`11 DESCRIPTION
`
`Cystadame (betaine anhydrous for oral solution) is an agent for the treatment ofhomocystinuria. It contains no ingredients other than anhydrous betaine. Cystadane
`is a white, granular, hygroscopic powder, which is diluted in water amd administered orally. The chemical name of betaine anhydrous powder is trimethylglycine. It
`has a molecular weight of 117.15. The structural formula is:
`
`CH3
`
`CH3
`I
`N+ -- CH2 -- COO "
`I
`CH3
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Cystadaaae acts as a methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. Cystadane occurs naturally in the
`body. It is a metabolite of choline and is present in small amounts in foods such as beets, spinach, cereals, and sea£ood.
`
`12.2 Pharmacodynamics
`
`Cystadaaae was observed to lower plasma homocysteine levels in three types of homocystinuria, including CBS deficiency; MTHFR deficiency; and cbl defect.
`Patients have taJ~en Cystadane for many years without evidence of tolerance. There has been no demonstrated correlation between Cystadane levels and homocysteine
`levels.
`
`In CBS-deficient patients, large increases in methionine levels over baseline have been observed. Cystadaaae has also been demonstrated to increase low- plasma
`methionine and S-adenosylmethionine (SAM) levels in patients with MTHFR deficiency and cbl defect.
`
`12.3 Pharmacokinetics
`
`Pharmacokinetic studies of Cystadaaae are not available. Plasma levels of Cystadane have not been measured in patients and have not been correlated to
`homocysteine levels.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Long-term ca~cinogenicity and fertility studies have not been conducted with Cystadane. No evidence of genotoxicity was demonstrated in the following tests:
`metaphase analysis of human lymphocytes; bacterial reverse mutation assay; and mouse micronucleus test.
`
`14 CLINICAL STUDIES
`
`Cystadaaae was studied in a double-blind, placebo-controlled, crossover study in 6 patients with CBS deficiency, ages 7 to 32 years at enrollment. Cystadaaae was
`administered at a dosage of 3 grams twice daily, for 12 months. Plasma homocystine levels were significantly reduced (p<0.01) compared to placebo. Plasma
`methionine levels were variable and not significaaatly different compared to placebo. No adverse events were reported in any patient.
`
`Cystadane has also been evaluated in observational studies without concurrent controls in patients with homocystinuria due to CBS deficiency, MTHFR deficiency,
`or cbl defect. A review- of 16 case studies aaad the randomized controlled trial previously described was also conducted, and the data available for each study were
`summarized; however, no formal statistical aaaalyses were performed. The studies included a total of 78 male and female patients with homocystinuria who were treated
`with Cystadane. This included 48 patients with CBS deficiency, 13 with MTHFR deficiency, and 11 with cbl defect, raaaging in age from 24 days to 53 years. The
`majority of patients (n 48) received 6 gin/day, 3 patients received less than 6 gin/day, 12 patients received doses from 6 to 15 gm/day, and 5 patients received doses
`over 15 gin/day. Most patients were treated for more thaaa 3 months (n 57) and 30 patients were treated for 1 yeax or longer (range 1 month to 11 years). Homocystine
`is formed nonenzymatically from two molecules of homocysteine, and both have be used to evaluate the effect of Cystadane in patients with homocystinuria. Plasma
`homocystine or homocysteine levels were reported numerically for 62 patients, and 61 of these patients showed decreases with Cystadaaae treatment. Homocystine
`decreased by 83-88% regardless ofpre-treatment level, aaad homocysteine decreased by 71-83%, regardless of the pre-treatment level. Clinical improvement, such as
`improvement in seizures, or behavioral and cognitive functioning, was reported by the treating physicians in about three-fourths of patients. Many of these patients
`were also taMng other therapies such as vitamin B6 (pyridoxine), vitamin B12 (cobalamin), and folate with vaxiable biochemical responses. In most cases, adding
`Cystadaaae resulted in a further reduction of either homocystine or homocysteine.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`Cystadaaae is available in plastic bottles containing 180 grams of betaine anhydrous. Each bottle is equipped with a plastic child-resistant cap and is supplied with a
`polystyrene measuring scoop. One level scoop (1.7 mL) is equal to 1 gram ofbetaine anhydrous powder.
`
`NDC 66621-4000-1
`
`180 g/bottle
`
`Cystadaaae can be ordered by calling Accredo Health Group, Inc., Customer service at 1-888-454-8860
`
`16.1 Storage
`
`Store at room temperature, 15 30 °C (59 86 °F). Protect from moisture.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1097-0003
`
`

`
`17 PATIENT COUNSELING INFORMATION
`
`Patients should be advised of the following information before beginning treatment with Cystadaaae:
`
`17.1 Dosing and Administration
`
`Instruct patients and caregivers that Cystadane should only be taken as directed by their healthcare professional.
`
`Instruct patients and caregivers to administer Cystadaaae as follows:
`
`¯
`
`¯
`
`¯
`Shake bottle lightly before removing cap.
`¯ Measure with the scoop provided.
`¯ Measure the number of scoops as prescribed by their healthcare professional. One level scoop (1.7 mL) is equivalent to 1 gram of betaine anhydrous
`powder.
`¯ Mix powder with 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula until completely dissolved, or mix with food, then ingest mixture
`immediately.
`Always replace the cap tightly after using, and protect powder from moisture.
`
`¯
`
`Distributed in the U.S. by:
`Rare Disease Therapeutics, Inc.
`2550 Meridiaaa Blvd., Suite 150
`Fraaaklin, TN 37067
`
`Paxt No.:
`
`RDT C PI003
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1097-0004