CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`20-645
`
`LABELING
`
`Par Pharmaceutical, Inc. Ex. 1015
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 1 of 20
`
`

`

`1 AMMONUL®
`(sodium phenylacetate and sodium benzoate) Injection
`2
`10% I 10%
`3
`4 Rx Only
`5
`6 DESCRIPTION
`7
`8 AMMONUL ®(sodium phenylacetate and sodium benzoate) Injection 10%/ 10% is a
`sterile, concentrated, aqueous solution of sodium phenylacetate and sodium benzoate, used
`9
`for the treatment ofhyperamrnonemia in urea cycle disorders. The pH of the solution is
`10
`between 6 and 8. Sodium phenylacetate is a crystalline, white to off-white powder with a
`11
`strong, offensive odor. It is soluble in water. Sodium benzoate is a white and odorless,
`12
`crystalline powder that is readily soluble in water.
`13
`14
`15
`
`Figure 1
`
`Sodium Phenylacetate
`
`Sodium Bel)zoate
`
`Sodium phenylacetate has a molecular weight of 158.13 and the molecular formula
`C8H7Na02. Sodium benzoate has a molecular weight of 144.11 and the molecular formula
`C7H5Na02.
`
`16
`17
`18
`19
`20
`Each mL of AMMO NUL® contains 100 mg of sodium phenylacetate and 100 mg of
`21
`sodium benzoate, and Water for Injection. Sodium hydroxide and/or hydrochloric acid
`22
`23 may have been used for pH adjustment.
`24
`25 AMMONUL ® injection is a sterile, concentrated solution intended for intravenous
`administration via a central line only after dilution (see DOSAGE AND
`26
`27 ADMINISTRATION). AMMONUL ®is packaged in single-use vials.
`28
`29 CLINICAL PHARMACOLOGY
`30
`31
`32
`33
`34
`35
`36
`
`Sodium phenylacetate and sodium benzoate are metabolically active compounds that can
`serve as alternatives to urea for the excretion of waste nitrogen. Phenylacetate conjugates
`with glutamine in the liver and kidneys to form phenylacetylglutamine, via acetylation.
`Phenylacetylglutamine is excreted by the kidneys via glomerular filtration and tubular
`secretion. The nitrogen content ofphenylacetylglutarnine per mole is identical to that of
`urea (both contain two moles of nitrogen). Similarly, preceded by acylation, benzoate
`
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`

`conjugates with glycine to form hippuric acid, which is rapidly excreted by the kidneys by
`glomerular filtration and tubular secretion. One mole of hippuric acid contains one mole
`of waste nitrogen. It has been shown that phenylacetylglutamine and hippurate can serve
`as alternative vehicles to effectively reduce waste nitrogen levels in patients with
`deficiencies of urea cycle enzymes and, thus, attenuate the risk of ammonia and glutamine-
`induced neurotoxicity.
`
`37
`38
`39
`40
`41
`42
`43
`44 Urea cycle disorders can result from decreased activity of any of the following enzymes:
`45 N-acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS),
`argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), argininosuccinate
`46
`lyase (ASL), or arginase (ARG). The most frequently observed initial presenting
`47
`symptoms in neonates include lethargy, seizures, poor feeding, neurologic changes,
`48
`edema, and respiratory distress. Patients with milder forms of enzyme deficiencies may
`49
`not present until late childhood, adolescence, or adulthood. Hyperammonemic crisis with
`50
`lethargy, delirium, and coma, in these patients, are often precipitated by viral illness, high
`51
`protein diet, stress, or trauma.
`52
`53
`Plasma and urine amino acid analyses are used to diagnose ASS and ASL and to provide a
`54
`preliminary diagnosis of CPS, OTC, or ARG. Blood citrulline levels are very low or
`55
`absent in OTC and CPS, very high in ASS, and normal to moderately high in ASL and
`56
`57 ARG. ASL may be distinguished by the presence ofhigh levels of the unusual amino acid
`argininosuccinic acid (ASA) in the urine. It should be noted, however, that ASA tends to
`58
`co-elute initially with other amino acids (such as leucine and isoleucine) in
`59
`chromatographs, and may be missed on initial examination. ARG is characterized by high
`60
`urine levels of arginine. A definitive diagnosis of CPS and OTC require a liver biopsy, and
`61
`red blood cell enzyme analysis is needed to confirm a diagnosis of ARG. Patients
`62
`suspected ofhaving a urea cycle disorder, based on family history, should have
`63
`documented hyperammonemia prior to administration of AMMONUL ® _
`64
`65
`66 Mechanism of Action
`67
`68
`69
`70
`71
`72
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`
`Figure 2 is a schematic illustrating how the components of AMMONUL ®, phenylacetate
`and benzoate, provide an alternative pathway for nitrogen dispQsal in patients without a
`fully functioning urea cycle. Two moles of nitrogen are removed per mole of
`phenylacetate when it is conjugated with glutamine, and one mole of nitrogen is removed
`per mole of benzoate when it is conjugated with glycine.
`
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`

`83
`
`Figure2
`O!·Ketoglutarate:
`NH"4
`Be_nyoate Gl clne ·~~I---~~~NH"4~Giutamate-\.,__ _____ ~ Glutamine Phenylac~tate
`y
`I Phenylacetylglutamlne
`
`HCOl
`
`ATP
`
`!Hippurate j
`
`[;P.~~~
`
`t
`. '
`Urine excretion
`.t..A
`' .
`'
`.
`'
`'
`
`Citrulline 1·-···/
`\ ._..,.!
`~r :
`Argininosucclnate 1--·/
`
`Arginine
`
`Fumarate
`
`Ornithine
`
`Supplemented • . • -"r
`Arginine
`. -··· ·
`
`84
`85
`86
`87
`88
`89
`90
`91
`92
`93
`94
`95
`96
`97
`Similarly, phenylacetate exhibited nonlinear kinetics following the priming dose regimens.
`98
`99 AUCtast was 175.b, 713.8, 2040.6, 2181.6, and 3829.2 mcg·hlmL following doses of 1, 2,
`3.75, 4, and 5.5 g/m2,respectively. The total clearance decreased from 1.82 to
`100
`0.89 mcg·hlmL with increasing dose (3.75 and 4 g/m2
`101
`, respectively).
`102
`103 During the sequence of90 minute priming infusion followed by a 24 hour maintenance
`infusion, phenylacetate was detected in the plasma at the end of infusion (T max of 2 hr at
`104
`· 3.75 g/m2
`) whereas, benzoate concentrations declined rapidly (Tmax of 1.5 hr at 3.75 g/m2
`105
`)
`and were undetectable at 14 and 26 b following the 3.75 and 4 g/m2 dose, respectively.
`106
`
`CPS= carbamyl phosphate synthetase; OTC =ornithine transcarbamylase; ASS = argininosuccinate synthetase; ASL =
`argininosuccinate lyase; ARG =arginase; NAGS= N-acetylglutamate synthetase
`
`Pharmacokinetics
`
`The pharmacokinetics of intravenously administered AMMONUL ®were characterized in
`healthy adult volunteers. Both benzoate and phenylacetate exhibited nonlinear kinetics.
`Following 90 minute intravenous infusion mean AUC!ast for benzoate was 20.3, 114.9,
`564.6, 562.8, and 1599.1 mcg/mL following doses of 1, 2, 3.75, 4, and 5.5 g/m2
`respectively. The total clearance decreased from 5.19 to 3.62 L/h/m2 at the 3.75 and 5.5
`g/m2 doses, respectively.
`
`,
`
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`

`The pharmacokinetics of intravenous phenylacetate have been reported following
`administration to adult patients with advanced solid tumors. The decline in serum
`phenylacetate concentrations following a loading infusion of 150 mg/kg was consistent
`with saturable enzyme kinetics. Ninety-nine percent of administered phenylacetate was
`excreted as phenylacetylglutamine [2,3).
`
`Special Populations
`
`Pharmacokinetic observations have also been reported from twelve episodes of
`hyperammonemic encephalopathy in seven children diagnosed (age 3 to 26 months) with
`urea cycle disorders who had been administered AMMO NUL® intravenously. These data
`showed peak plasma levels of phenylacetate and benzoate at approximately the same times
`as were observed in adults. As in adults, the plasma levels of phenylacetate were higher
`than benzoate and were present for a longer time [1].
`
`107
`108 A difference in the metabolic rates for phenylacetate and benzoate was noted. The
`formation of hippurate from benzoate occurred more rapidly than that of
`109
`phenylacetylglutamine from phenylacetate, and the rate of elimination for hippurate
`110
`appeared to be more rapid than that for phenylacetylglutamine.
`111
`112
`113
`114
`11 s
`116
`117
`118
`119
`120
`121
`122
`123
`124
`125
`126
`127
`128 Gender:
`Pharmacokinetic parameters of AMMO NUL® were compared in healthy males and
`129
`females. Bioavailability of both benzoate and phenylacetate was slightly higher in females
`130
`than in males. However, conclusions cannot be drawn due to the limited number of
`131
`subjects in this study.
`132
`133
`134 Hepatic Insufficiency:
`Limited information is available on the metabolism and excretion of sodium phenylacetate
`135
`and sodium benzoate in patients with impaired hepatic function. However, as the liver is
`136
`one of the two organs (the other is the kidney) in which the metabolic conjugation of
`137
`sodium phenylacetate and sodium benzoate is known to take place, care should be used in
`138
`administering AMMONUL ®to patients with hepatic insufficiency.
`139
`140
`141
`142
`143
`144
`145
`146 Dialysis:
`Intravenous use of AMMONUL ®is complementary with the use of dialysis[4,5].
`147
`In the non-neonatal study patient population treated with AMMONUL ®' dialysis (standard
`148
`hemodialysis, peritoneal dialysis, arteriovenous hemofiltration, or other dialysis) was
`149
`required in 13% of hyperammonemic episodes. Standard hemodialysis was the most
`150
`frequently used dialysis method. High levels of ammonia can be reduced quickly when
`151
`
`Renal Impairment:
`For effective AMMONUL ®drug therapy, renal clearance of the drug metabolites and
`subsequently ~mmonia is required. Therefore, patients with impaired renal function
`should be closely monitored.
`
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`152 AMMONUL ®is used with dialysis, as the ammonia-scavenging of AMMONUL ®
`suppresses the production of ammonia from catabolism of endogenous protein[6] and
`153
`dialysis eliminates the ammonia and ammonia conjugates.
`154
`155
`156 Drug Interactions:
`Formal drug interaction studies have not been performed with AMMONUL ®_
`157
`158
`159
`160
`In patients with hyperammonemia due to deficiencies in enzymes of the urea cycle,
`161
`162 AMMONUL ®has been shown to decrease elevated plasma ammonia Levels and improve
`encephalopathy and survival outcome compared to historical controls. These effects are
`163
`considered to be the result of reduction in nitrogen overload through glutamine and glycine
`164
`scavenging by AMMONUL ®in combination with appropriate dietary and other supportive
`165
`166 measures.
`167
`168
`169
`170
`171
`172
`173
`174
`175
`176
`177
`
`The efficacy of AMMONUL ® in improving patient survival of acute hyperammonemic
`episodes was demonstrated in an analysis of316 patients (1045 episodes of
`hospitalization) treated between 1981 and 2003.
`
`Pharmacodynamics
`
`Clinical Data
`
`The demographic characteristics and diagnoses of the patient population are shown in
`Table 1.
`
`Table 1
`
`r Ch
`l
`.
`B
`ase me
`aracterishcs an dD iagnoses o fS d P
`tu ly
`opu atlon
`Patients*
`N=316
`Male
`158 (51%)
`Female
`150 (49%)
`N
`310
`Mean (SD)
`6.2 (8.54)
`Min- Max
`0.0- 53.0
`0-30 days
`104 (34%)
`31 days- 2 years
`55 (18%)
`> 2-12 years
`90 (29%)
`> 12- 16 years
`30 (10%)
`> 16 years
`31 (10%)
`OTC
`146 (46%)
`ASS
`71 (22%)
`CPS
`38 (12%)
`ASL
`7(2%)
`ARG
`2 (< 1%)
`THN
`2(<1%)
`Other**
`56 (18%)
`OTC = omithme transcarbamylase deficiency; ASS = argminosuccmate synthetase deficiency; CPS=
`carbamyl phosphate synthetase deficiency; ASL = argininosuccinate lyase deficiency; ARG = arginase
`deficiency; THN = transient hyperamrnonemia of the newborn
`
`Gender
`
`Age (years)
`
`Age groups
`
`Enzyme deficiency
`
`178
`179
`180
`
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`Survival was substantially improved after Ammonul treatment compared with historical
`values (estimated 14% 1-year survival rate with dietary therapy alone) [10] and with
`dialysis (estimated 43% survival of acute hyperammonemia) [11].
`
`*For the summary at the patient level, data obtained at first episode used.
`**Diagnosis unknown or pending (33 episodes), acidemia (14 episodes), IlliH syndrome (6 episodes),
`carnitine translocase deficiency (4 episodes), liver disease (3 episodes), HMG CoA lyase deficiency (1
`episode), non-ketotic hyperg1ycinemia (I episode), suspected fatty acid ·oxidation deficiency ( 1 episode), and
`va1proic-acid-induced hyperammonemia ( 1 episode).
`
`181
`182
`183
`184
`185
`186
`187 On admission to the hospital, patients with hyperammonemia or a potential urea cycle
`disorder (UCD) were treated with a bolus dose of0.25 glkg (or 5.5 .g/m2
`188
`) sodium
`phenylacetate + 0.25 glkg (or 5.5 g/m2
`189
`) sodium benzoate over a period of 90 minutes to 6
`hours, depending on the specific UCD. Infusions also contained arginine; the dose of
`190
`arginine depended on the specific UCD. After completion of the bolus dose, maintenance
`191
`infusions of the same dose over 24 hours were continued until the patient was no longer
`192
`hyperammonemic or oral therapy could be tolerated. The mean (SD) duration of treatment
`193
`194 was 4.6 (6.45) days per episode, and ranged from 1 to 72 days.
`195
`196
`197
`198
`199
`200 Ninety-four percent (981 of 1045) ofhyperamrnonemic episodes treated with
`AMMO NUL® resulted in patients being discharged from the hospital. Eighty percent of
`201
`patients (252 of316) survived their last episode. Of the 64 patients who died, 53 (83%)
`202
`died during their first hyperammonemic episode. Of the I 04 neonates ( <30d) treated with
`203
`204 AMMONUL ®' 34 (33%) died during the first hyperammonemic episode.
`205
`206 Ammonia levels decreased from very high levels(> 4 times the upper limit of normal
`[ULN]) to lower levels in 91% of episodes after treatment. In patients responding to
`207
`therapy, mean ammonia concentrations decreased significantly within four hours of
`208
`initiation of AMMO NUL® therapy and were maintained. Dialysis is recommended for
`209
`21 o
`those patients who fail to have a significant reduction in plasma ammonia levels within 4
`to 8 hours after receiving AMMONUL ®. A shift from high(~ 4 times ULN) to very high
`211
`(> 4 times ULN) levels was observed in only 4% of the episodes.
`212
`213
`Improvements in neurological status endpoints were observed in most episodes and
`214
`patients. Overall, investigators rated neurological status as improved, much improved, or
`215
`the same in 93% of episodes, and overall status in response to treatment as improved,
`216
`217 much improved, or the same in 97% of episodes. Recovery from coma was observed in
`97% of episodes where coma was present at admission (111 of 114 episodes).
`218
`219
`220
`221
`222
`223
`224 AMMONUL ® is indicated as adjunctive therapy for the treatment of acute
`hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes
`225
`of the urea cycle. In acute neonatal hyperamrnonemic coma, in moderate to severe
`226
`
`INDICATIONS AND USAGE
`
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`CONTRAINDICATIONS
`
`episodes ofhyperammonemic encephalopathy, and in episodes ofhyperammonemia which
`fail to respond to an initial course of ~ONUL ®therapy, hemodialysis is the most rapid
`and effective technique for removing an:nnonia [12,13]. In such cases, the concomitant
`administration of AMMONUL ® can help prevent the re-accumulation of ammonia by
`increasing waste nitrogen excretion [4,5,13] .
`
`227 ·
`228
`229
`230
`231
`232
`233
`234
`235 AMMONUL ® should not be administered to patients with known hypersensitivity to
`sodium phenylacetate or sodium benzoate.
`236
`237
`238 WARNINGS
`239
`240 Any episode of acute symptomatic hyperammonemia should be treated as a life-
`threatening emergency. Treatment of hyperammonemia may require dialysis,
`241
`preferably hemodialysis, to remove a large burden of ammonia. Uncontrolled
`242
`hyperammonemia can rapidly result in brain damage or death, and prompt use of all
`243
`therapies necessary to reduce ammonia levels is essential.
`244
`245
`246 Management ofhyperammonemia due to inborn errors of metabolism should be done in
`coordination with medical personnel familiar with these diseases. The severity of the
`247
`disorder may necessitate the use of hemodialysis combined with nutritional management
`248
`and medical support. The multidisciplinary nature of the treatment usually requires the
`249
`facilities of a tertiary or quaternary care center.
`250
`251
`252 Ongoing monitoring of plasma ammonia levels, neurological status, laboratory tests, and
`clinical response in patients receiving AMMONUL ®is crucial to assess patient response
`253
`to treatment. Because urine potassium loss is enhanced by the excretion of the non-
`254
`reabsorbable anions, phenylacetylglutamine and hippurate, plasma potassium levels should
`255
`be carefully monitored and appropriate treatment given when necessary. Serum
`256
`electrolyte levels should be monitored and maintained within the normal range.
`257
`258
`259 AMMONUL ®contains 30.5 mg of sodium per mL of undiluted product. Thus,
`260 AMMONUL ®should be used with great care, if at all, in patients with congestive heart
`failure or severe renal insufficiency, and in clinical states in which there is sodium
`261
`retention with edema. If an adverse reaction does occur, discontinue administration of
`262
`AMMONUL ®,evaluate the patient, and institute appropriate therapeutic countermeasures.
`263
`264
`265 Administration must be through a central line. Administration through a peripheral
`line may cause burns.
`266
`Bolus infusion flow rates are relatively high, especially for infants (see DOSAGE AND
`267
`268 ADMINISTRATION). Extravasation of AMMONUL ®into the perivenous tissues may
`lead to skin necrosis. If extravasation is suspected, discontinue the infusion and resume at
`269
`a different infusion site, if necessary. Standard treatment for extravasation can include
`270
`aspiration of residual drug from the catheter, limb elevation, and intermittent cooling using
`271
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`

`cold packs [14]. The infusion site must be monitored closely for possible infiltration
`during drug administration. Do not administer undiluted product.
`
`PRECAUTIONS
`
`Because of prolonged plasma levels achieved by phenylacetate in pharmacokinetic
`studies, repeat loading doses of AMMONUL ®should not be administered.
`
`272
`273
`274
`275 Due to structural similarities between phenylacetate and benzoate to salicylate,
`276 AMMONUL ®may cause side effects typically associated with salicylate overdose, such as
`hyperventilation and metabolic acidosis. The clinician is advised to perform blood
`277
`chemistry profiles, and frequent blood pH and pC02 monitoring.
`278
`279
`280
`281
`282 General:
`283 AMMONUL ® is a concentrated solution and must be diluted before administration via a
`central line. Because sodium phenylacetate and sodium benzoate are metabolized in the
`284
`liver and kidney, and since phenylacetylglutamine and hippurate are primarily excreted by
`285
`the kidney, use caution when administering AMMONUL ® to patients with hepatic or renal
`286
`insufficiency. AMMONUL ® infusion has been associated with nausea and vomiting. An
`287
`antiemetic may be administered during AMMONUL ® infusion.
`288
`289
`290
`291
`292
`293 Use of corticosteroids may cause the breakdown of body protein and, thereby, potentially
`increase plasma ammonia levels in patients with impaired ability to form urea.
`294
`295
`296 Neurotoxicity of Phenylacetate:
`297 Neurotoxicity was reported in cancer patients receiving intravenous phenylacetate,
`250-300 mg/kg/day for 14 days, repeated at 4-week intervals. Manifestations were
`298
`predominantly somnolence, fatigue, and lightheadedness, with·less frequent headaches,
`299
`dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of a pre-
`300
`existing neuropathy. These adverse events were mainly mild. The acute onset of
`301
`symptoms upon initiation of treatment and reversibility of symptoms when the
`302
`phenylacetate was discontinued suggest a drug effect [2,3).
`303
`304
`305
`306
`307
`308
`309
`310
`311
`312
`313
`3 14
`315
`316 Drug Interactions:
`
`In animal studies, subcutaneous administration to rat pups of 190-474 mg/kg of
`phenylacetate caused decreased proliferation and increased loss of neurons, and reduced
`central nervous system (CNS) myelin. Cerebral synapse maturation was retarded, and the
`number of functioning nerve terminals in the cerebrum was reduced, which resulted in
`impaired brain growth [15] . Pregnant rats were given phenylacetate at 3.5 J..Lmol/g/day
`subcutaneous from gestation day 7 through normal delivery. Prenatal exposure of rat pups
`to phenylacetate produced lesions in layer 5 cortical pyramidal cells; dendritic spines were
`longer and thinner than normal and reduced in number {16].
`
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`

`There have been reports that valproic acid can induce hyperamrnonemia through inhibition
`of the synthesis ofN-acetylglutamate, a co-factor for carbamyl phosphate synthetase [14).
`Therefore, administration of valproic acid to patients with urea cycle disorders may
`exacerbate their condition and antagonize the efficacy of AMMONUL ®[15].
`
`Labor and Delivery:
`The effects of AMMONUL ® on labor and delivery are unknown.
`
`Some antibiotics such as penicillin may compete with phenylacetylglutamine and
`hippurate for active secretion by renal tubules, which may affect the overall disposition of
`the infused drug.
`
`Probenecid is known to inhibit the renal transport of many organic compounds, including
`aminohippuric acid, and may affect renal excretion ofphenylacetylglutamine and
`hippurate [13).
`
`317
`318
`319
`320
`321
`322
`323
`324
`325
`326
`327
`328
`329 -
`330 Carcinogenesis, Mutagenesis, Impairment of Fertility:
`Carcinogenicity, mutagenicity and fertility studies of sodium phenylacetate have not been
`331
`conducted. Sodium benzoate has been extensively tested as a food preservative. Results
`332
`indicate that sodium benzoate is not mutagenic or carcinogenic, and does not impair
`333
`fertility.
`334
`335
`Pregnancy:
`336
`Pregnancy Category C. Animal reproduction studies have not been conducted with
`337
`338 AMMONUL ®_ It is not known whether AMMONUL ® can cause fetal harm when
`administered to a pregnant woman or can affect reproduction capacity. Thus,
`339
`340 AMMO NUL® should be given to a pregnant woman only if clearly needed.
`341
`342
`343
`344
`345
`346 Nursing Mothers:
`It is not known whether sodium phenylacetate, sodium benzoate, or their conjugation
`347
`products are excreted in human milk. Because many drugs are excreted in human milk,
`348
`caution should be exercised when AMMONUL ® is administered to a nursing woman.
`349
`350
`Pediatric:
`351
`352 AMMONUL ®has been used as a treatment for acute hyperammonemia in pediatric
`patients including patients in the early neonatal period (see DOSAGE AND
`353
`354 ADMINISTRATION).
`355
`356 ADVERSE REACTIONS
`357
`358
`359
`360
`361
`
`The safety data were obtained from 316 patients who received AMMONUL® as
`emergency (rescue) or prospective treatment for hyperammonemia as part of an
`uncontrolled, open-label study. The study population included patients between the ages
`of 0 to 53 years with a mean (SD) of6.2 (8.54) years; 51% were male and 49% were
`
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`

`female who had the following diagnoses: OTC (46%), ASS (22%), CPS (12%), ASL
`(2%),ARG(< 1%), THN(< 1%),andother(l8%).
`
`a e
`T bl 2
`
`Ad verse E ven ts O
`. > 3"1«
`ccurnng m
`f P ti
`t T
`a ens rea e WI
`t d
`"th A
`mmonu l
`o O
`Patients
`N=316
`163 (52%)
`35 (11%)
`12 (4%)
`11 (3o/ol
`28 (9%)
`42 (13%)
`10 (3%)
`9 (3%)
`29 (9%)
`45 (14%)
`11 (3%)
`17 (5%)
`39 (12%)
`9 (3%)
`12 (4%)
`32 (10%)
`67 (21%)
`8 (3%)
`17 (5%)
`22 (7%)
`8 (3%)
`23 (7%)
`13 (4%)
`71 (22%)
`17 (5%)
`10 (3%)
`19 (6%)
`18 (6%)
`16 (5%)
`8 (3%)
`14 (4%)
`47 (15%)
`9 (3%)
`19 (6%)
`19 (6%)
`14 (4%)
`
`No. patients with any adverse event
`Blood and lymphatic system disorders
`Anemia NOS
`Disseminated intravascular coagulation
`Cardiac disorders
`Gastrointestinal disorders
`Diarrhea NOS
`Nausea
`Vomiting NOS
`General disorders and administration-site conditions
`Injection-site reaction NOS
`Pyrexia
`infections
`Urinary tract infection NOS
`Injury, poisoning and procedural complications
`Investigations
`Metabolism and nutrition disorders
`Acidosis NOS
`Hyperammonemia
`Hyperglycemia NOS
`Hypocalcemia
`Hypokalemia
`Metabolic acidosis NOS
`Nervous system disorders
`Brain edema
`Coma
`Convulsions NOS
`Mental impairment NOS
`Psychiatric disorders
`Agitation
`Renal and urinary disorders
`Respiratory, thoracic and mediastinal disorders
`Respiratqry distress
`Skin and subcutaneous tissue disorders
`Vascular disorders
`Hypotension NOS
`
`362
`363
`364
`365
`
`366
`
`Clinically Important Adverse Reactions
`367
`368 Adverse events occurred most frequently in the following system organ classes: nervous
`system disorders (22% of patients), metabolism and nutrition disorders (21% of patients),
`369
`and respiratory, thoracic and mediastinal disorders (15% of patients). The most frequently
`370
`reported adverse events were vomiting (9% of patients), hyperglycemia (7% of patients),
`371
`
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`372
`373
`
`hypokalemia (7% of patients), convulsions (6% of patients), and mental impairment (6%
`ofpatients).
`
`Subpopulation and Risk Factor Data
`
`374
`375 Adverse events leading to study drug discontinuation occurred in 4% of patients.
`376 Metabolic acidosis and injection-site reactions each led to discontinuation in 2 patients
`(< 1 %). Adverse events leading to discontinuation in 1 patient included bradycardia,
`377
`abdominal distension, injection-site extravasation, injection-site hemorrhage, blister,
`378
`overdose, subdural hematoma, hyperammonemia, hypoglycemia, clonus, coma, increased
`379
`intercranial pressure, hypercapnia, Kussmaul respiration, respiratory distress, respiratory
`380
`failure, pruritis, and maculo-papular rash.
`381
`382
`383
`384
`385 Adverse events were reported with similar frequency in patients with OTC, ASS, CPS, and
`diagnoses categorized as "other." Nervous system disorders were more frequent in
`386
`patients with OTC and CPS, compared with patients with ASS and patients with "other"
`387
`diagnoses. Convulsions and mental impainnent were reported in patients with OTC and
`388
`CPS. These observations are consistent with literature reports that patients with enzyme
`389
`deficiencies occurring earlier in the urea cycle (i.e., OTC and CPS) tend to be more
`390
`severely affected.
`391
`392
`393 Adverse event profiles did differ by age group. Patients ~ 30 days of age had more blood
`and lymphatic system disorders and vascular disorders (specifically hypotension), while
`394
`patients> 30 days of age had more gastrointestinal disorders (specifically nausea,
`395
`vomiting and diarrhea).
`396
`397
`398 Other Less Common Adverse Events Occurring in< 3% of Patients
`Less common adverse events that could represent drug-induced reactions or are
`399
`characterized as severe are listed below by body system.
`400
`BLOOD AND LYMPHATIC SYSTEM DISORDERS: coagulopathy, pancytopenia,
`thrombocytopenia
`CARDIAC DISORDERS: atrial rupture, cardiac or cardiopulmonary arrest/failure,
`cardiogenic shock, cardiomyopathy, pericardia! effusion
`EYE DISORDERS: blindness
`406 GASTROINTESTINAL DISORDERS: gastrointestinal hemorrhage
`407 GENERAL DISORDERS AND ADMINISTRATION-SITE CONDITIONS: asthenia,
`brain death, chest pain, multiorgan failure, edema
`408
`409 HEPATOBILIARY DISORDERS: cholestasis, hepatic artery stenosis, hepatic failure/
`41 o
`hepatotoxicity, jaundice
`INFECTIONS AND INFESTATIONS: sepsis/septic shock
`INJURY, POISONING AND PROCEDURAL COMPLICATIONS: brain herniation,
`subdural hematoma
`
`401
`402
`
`403
`404
`
`405
`
`411
`
`412
`413
`
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`422
`423
`
`424
`
`425
`426
`427
`428
`
`429
`430
`
`INVESTIGATIONS: blood carbon dioxide changes, blood glucose changes, blood pH
`414
`increased, cardiac output decreased, pC02 changes, respiratory rate increased
`415
`416 METABOLISM AND NUTRITION DISORDERS: alkalosis, dehydration, fluid
`overload/retention, hyperkalemia, hypematremia, alkalosis, tetany
`417
`418 NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED: hemangioma acquired
`419 NERVOUS SYSTEM DISORDERS: areflexia, ataxia, brain infarction, brain hemorrhage,
`cerebral atrophy, clonus, depressed level of consciousness, encephalopathy, nerve
`420
`paralysis, intracranial pressure increased, tremor
`421
`PSYCHIATRIC DISORDERS: acute psychosis, aggression, confusional state,
`hallucinations
`RENAL AND URINARY DISORDERS: anuria, renal failure, urinary retention
`RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: acute respiratory
`distress syndrome, dyspnea, hypercapnia, hyperventilation, Kussmaul respiration,
`pneumonia aspiration, pneumothorax, pulmonary hemorrhage, pulmonary edema,
`respiratory acidosis or alkalosis, respiratory arrest/failure
`SKIN AND SUBCUTANEOUS TISSUE DISORDERS: alopecia, pruritis generalized,
`rash, urticaria
`VASCULAR DISORDERS: flushing, hemorrhage, hypertension,
`phlebothrombosis/thrombosis
`
`431
`432
`433
`434 OVERDOSAGE
`435
`436 Overdosage has been reported during AMMONUL ® treatment in urea cycle-deficient
`patients [17). All patients in the uncontrolled open-label study were to be treated at the
`437
`same dose of AMMONUL ®_ However, some patients received more than the dose level
`438
`specified in the protocol. In 16 of the 64 deaths, the patient received a known overdose of
`439
`440 AMMONUL ®_ Causes of death in these patients included cardiorespiratory failure/arrest
`(6 patients), hyperammonemia (3 patients), increased intracranial pressure (2 patients),
`441
`pneumonitis with septic shock and coagulopathy (1 patient), error in dialysis procedure (1
`442
`patient), respiratory failure (1 patient), intractable hypotension and probable sepsis (1
`443
`patient), and unknown (I patient). Additionally, other signs of intoxication may include
`444
`obtundation (in the absence ofhyperammonemia), hyperventilation, a severe compensated
`445
`446 metabolic acidosis, perhaps with a respiratory component, large anion gap, hypernatremia
`and hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and death.
`447
`448
`449
`450
`451
`452
`453
`454
`455
`
`In case of overdose of AMMONUL ®, discontinue the drug and institute appropriate
`emergency medical monitoring and procedures. In severe cases, the latter may include
`hemodialysis (procedure of choice) or peritoneal dialysis (when hemodialysis is
`unavailable) [17].
`
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`General
`
`456 DOSAGE AND ADl\1INISTRA TION
`457
`:458 Administration must be through a central line. Administration through a peripheral
`line may cause burns.
`459
`460
`461
`462
`463 AMMONUL ® is administered intravenously as a loading dose infusion administered over
`90 to 120 minutes, followed by an equivalent maintenance dose infusion administered over
`464
`24 hours. AMMONUL ® may not be administered by any other route. Administration of
`465
`analogous oral drugs, such as Buphenyl® (sodium phenylbutyrate), should be terminated
`466
`prior to AMMONUL ®infusion.
`467
`468
`469 Hyperammonemic coma (regardless of cause) in the newborn infant should be
`aggressively treated while the specific diagnosis is pursued. All patients should be
`470
`promptly hemodialyzed as the procedure of choice using the largest catheters consistent
`471
`472 with the patient's size. A target blood flow of 150 mL/min/m2 may be attained using a 7F
`catheter. (Ammonia clearance [mL/min] is similar to the blood flow rate [mL/min] through
`473
`the dialyzer). Clearance of ammonia is approximately ten times greater by hemodialysis
`474
`than by peritoneal dialysis or hemofiltration. Exchange transfusion is ineffective in the
`475
`476