Sodium Oxybate

1 INDICATIONS AND USAGE Sodium oxybate oral solution is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy. Pediatric use information is approved for Jazz Pharmaceuticals Inc.’s XYREM (sodium oxybate) Oral Solution. However, due to Jazz Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Sodium oxybate oral solutio n is a central nervous system depressant indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy (1).

2 DOSAGE AND ADMINISTRATION Dosage for Adult Patients Initiate dosage at 4.5 g per night orally, divided into two doses ( 2.1 ). Titrate to effect in increments of 1.5 g per night at weekly intervals (0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) ( 2.1 ). Recommended dosage range: 6 g to 9 g per night orally ( 2.1 ). Total Nightly Dose Take at Bedtime Take 2.5 to 4 Hours Later 4.5 g per night 2.25 g 2.25 g 6 g per night 3 g 3 g 7.5 g per night 3.75 g 3.75 g 9 g per night 4.5 g 4.5 g Important Administration Information Prepare both doses prior to bedtime; dilute each dose with approximately ¼ cup of water in pharmacy-provided containers ( 2.3 ). Allow 2 hours after eating before dosing ( 2.3 ). Take each dose while in bed and lie down after dosing ( 2.3 ). Patients with Hepatic Impairment Recommended starting dosage is one-half of the original dosage per night administered orally, divided into two doses ( 2.4 ). 2.1 Adult Dosing Information The recommended starting dosage is 4.5 grams (g) per night administered orally, divided into two doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dosage by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dosage range of 6 g to 9 g per night orally. The dosage may be gradually titrated based on efficacy and tolerability. Doses higher than 9 g per night have not been studied and should not ordinarily be administered. Table 1: Recommended Adult Sodium oxybate oral solution Dose Regimen (g = grams) If a Patient’s Total Nightly Dose is: Take at Bedtime: Take 2.5 to 4 Hours Later: 4.5 g per night 2.25 g 2.25 g 6 g per night 3 g 3 g 7.5 g per night 3.75 g 3.75 g 9 g per night 4.5 g 4.5 g Pediatric use information is approved for Jazz Pharmaceuticals Inc.’s XYREM (sodium oxybate) Oral Solution. However, due to Jazz Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.3 Important Administration Instructions for All Patients The total nightly dosage of sodium oxybate oral solution is divided into two doses. Prepare both doses of sodium oxybate oral solution prior to bedtime. Prior to ingestion, each dose of sodium oxybate oral solution should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy containers provided. Take the first nightly dose of sodium oxybate oral solution at least 2 hours after eating [see Clinical Pharmacology (12.3)]. Take the second nightly dose 2.5 to 4 hours after the first dose. Patients should take both doses of sodium oxybate oral solution while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. Sodium oxybate oral solution may cause patients to fall asleep abruptly without first feeling drowsy [see Adverse Reactions (6.2)]. Patients will often fall asleep within 5 minutes of taking sodium oxybate oral solution, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep. If the second dose is missed, that dose should be skipped and sodium oxybate oral solution should not be taken again until the next night. Both sodium oxybate oral solution doses should never be taken at one time. 2.4 Dosage Modification in Patients with Hepatic Impairment The recommended starting dosage in patients with hepatic impairment is one-half of the original dosage per night, administered orally divided into two doses [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 2.5 Dosage Adjustment with Co-administration of Divalproex Sodium When initiating divalproex sodium in patients taking a stable dosage of sodium oxybate oral solution, a reduction of the sodium oxybate oral solution dosage by at least 20% is recommended with initial concomitant use [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. When initiating sodium oxybate oral solution in patients already taking divalproex sodium, a lower starting dosage of sodium oxybate oral solution is recommended. Subsequently, the dosage of sodium oxybate oral solution can be adjusted based on individual clinical response and tolerability.

4 CONTRAINDICATIONS Sodium oxybate oral solution is contraindicated for use in: combination with sedative hypnotics [see Warnings and Precautions (5.1)]. combination with alcohol [see Warnings and Precautions (5.1)]. patients with succinic semialdehyde dehydrogenase deficiency [see Clinical Pharmacology (12.3)]. In combination with sedative hypnotics or alcohol ( 4 ) Succinic semialdehyde dehydrogenase deficiency ( 4 )

5 WARNINGS AND PRECAUTIONS CNS depression: Use caution when considering the concurrent use of sodium oxybate oral solution with other CNS depressants (5.1). Caution patients against hazardous activities requiring complete mental alertness or motor coordination within the first 6 hours of dosing or after first initiating treatment until certain that sodium oxybate oral solution does not affect them adversely (5.1). Depression and suicidality: Monitor patients for emergent or increased depression and suicidality (5.5). Confusion/Anxiety: Monitor for impaired motor/cognitive function (5.6). Parasomnias: Evaluate episodes of sleepwalking (5.7). High sodium content in sodium oxybate oral solution: Monitor patients with heart failure, hypertension, or impaired renal function (5.8). 5.1 Central Nervous System Depression Sodium oxybate is a central nervous system (CNS) depressant. In adult clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in patients treated with sodium oxybate oral solution. Sodium oxybate oral solution is contraindicated in combination with alcohol and sedative hypnotics. The concurrent use of sodium oxybate oral solution with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with sodium oxybate oral solution is required, dose reduction or discontinuation of one or more CNS depressants (including sodium oxybate oral solution) should be considered. In addition, if short-term use of an opioid (e.g., post- or perioperative) is required, interruption of treatment with sodium oxybate oral solution should be considered. Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that sodium oxybate oral solution does not affect them adversely (e.g., impair judgment, thinking, or motor skills). Patients should not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination, such as operating machinery or a motor vehicle or flying an airplane, for at least 6 hours after taking sodium oxybate oral solution. Patients should be queried about CNS depression-related events upon initiation of sodium oxybate oral solution therapy and periodically thereafter. Sodium oxybate oral solution is available only through a restricted program under a REMS [see Warnings and Precautions (5.3)]. 5.2 Abuse and Misuse Sodium oxybate oral solution is a Schedule III controlled substance. The active ingredient of sodium oxybate oral solution, sodium oxybate or gamma-hydroxybutyrate (GHB), is a Schedule I controlled substance. Abuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death. The rapid onset of sedation, coupled with the amnestic features of sodium oxybate oral solution, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g., assault victim). Because illicit use and abuse of GHB have been reported, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of GHB (e.g., increase in size or frequency of dosing, drug-seeking behavior, feigned cataplexy) [see Drug Abuse and Dependence (9.2)]. Sodium oxybate oral solution is available only through a restricted program under a REMS [see Warnings and Precautions (5.3)]. 5.3 Sodium Oxybate REMS Program Sodium oxybate oral solution is available only through a restricted distribution program called the Sodium Oxybate REMS Program because of the risks of central nervous system depression and abuse and misuse [see Warnings and Precautions (5.1, 5.2)]. Notable requirements of the Sodium Oxybate REMS Program include the following: Healthcare Providers who prescribe sodium oxybate are specially certified Sodium oxybate oral solution will be dispensed only by the certified pharmacy that is specially certified Sodium oxybate oral solution will be dispensed and shipped only to patients who are enrolled in the Sodium Oxybate REMS Program with documentation of safe use Further information is available at www.SOXREMSProgram.com or 1-833-769-7367 (1-833-SOX-REMS). 5.4 Respiratory Depression and Sleep-Disordered Breathing Sodium oxybate oral solution may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported [see Overdosage (10)]. In an adult study assessing the respiratory-depressant effects of sodium oxybate oral solution at doses up to 9 g per night in 21 patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four patients with preexisting, moderate-to-severe sleep apnea had significant worsening of the apnea/hypopnea index during treatment. In an adult study assessing the effects of sodium oxybate oral solution 9 g per night in 50 patients with obstructive sleep apnea, sodium oxybate oral solution did not increase the severity of sleep-disordered breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central apneas in patients taking sodium oxybate oral solution, and clinically significant oxygen desaturation (≤ 55%) was measured in three patients (6%) after sodium oxybate oral solution administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation. Prescribers should be aware that increased central apneas and clinically relevant desaturation events have been observed with sodium oxybate oral solution administration in adult patients. In adult clinical trials in 128 patients with narcolepsy, two subjects had profound CNS depression, which resolved after supportive respiratory intervention. Two other patients discontinued sodium oxybate because of severe difficulty breathing and an increase in obstructive sleep apnea. In two controlled trials assessing PSG measures in adult patients with narcolepsy, 40 of 477 patients were included with a baseline apnea/hypopnea index of 16 to 67 events per hour, indicative of mild to severe sleep-disordered breathing. None of the 40 patients had a clinically significant worsening of respiratory function as measured by apnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 g per night. Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients, in men, in postmenopausal women not on hormone replacement therapy and among patients with narcolepsy. Pediatric use information is approved for Jazz Pharmaceuticals Inc.’s XYREM (sodium oxybate) Oral Solution. However, due to Jazz Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 5.5 Depression and Suicidality In adult clinical trials in patients with narcolepsy (n=781), there were two suicides and two attempted suicides in patients treated with sodium oxybate oral solution, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used sodium oxybate oral solution in conjunction with other drugs. Sodium oxybate oral solution was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 patients treated with sodium oxybate oral solution, with four patients (<1%) discontinuing because of depression. In most cases, no change in sodium oxybate oral solution treatment was required. In a controlled adult trial, with patients randomized to fixed doses of 3 g, 6 g, or 9 g per night sodium oxybate oral solution or placebo, there was a single event of depression at the 3 g per night dose. In another adult controlled trial, with patients titrated from an initial 4.5 g per night starting dose, the incidences of depression were 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%) for the placebo, 4.5 g, 6 g, and 9 g per night doses, respectively. The emergence of depression in patients treated with sodium oxybate oral solution requires careful and immediate evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be monitored carefully for the emergence of depressive symptoms while taking sodium oxybate oral solution. Pediatric use information is approved for Jazz Pharmaceuticals Inc.’s XYREM (sodium oxybate) Oral Solution. However, due to Jazz Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 5.6 Other Behavioral or Psychiatric Adverse Reactions During adult clinical trials in patients with narcolepsy, 3% of 781 patients treated with sodium oxybate oral solution experienced confusion, with incidence generally increasing with dose. Less than 1% of patients discontinued the drug because of confusion. Confusion was reported at all recommended doses from 6 g to 9 g per night. In a controlled trial in adults where patients were randomized to fixed total daily doses of 3 g, 6 g, or 9 g per night or placebo, a dose-response relationship for confusion was demonstrated, with 17% of patients at 9 g per night experiencing confusion. In all cases in that controlled trial, the confusion resolved soon after termination of treatment. In Trial 3 where sodium oxybate was titrated from an initial 4.5 g per night dose, there was a single event of confusion in one patient at the 9 g per night dose. In the majority of cases in all adult clinical trials in patients with narcolepsy, confusion resolved either soon after termination of dosing or with continued treatment. Anxiety occurred in 5.8% of the 874 patients receiving sodium oxybate oral solution in adult clinical trials in another population. Other neuropsychiatric reactions reported in adult clinical trials in patients with narcolepsy and the post-marketing setting included hallucinations, paranoia, psychosis, aggression, and agitation. The emergence or increase in the occurrence of behavioral or psychiatric events in adult patients taking sodium oxybate oral solution should be carefully monitored. Pediatric use information is approved for Jazz Pharmaceuticals Inc.’s XYREM (sodium oxybate) Oral Solution. However, due to Jazz Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 5.7 Parasomnias Sleepwalking, defined as confused behavior occurring at night and at times associated with wandering, was reported in 6% of 781 patients with narcolepsy treated with sodium oxybate oral solution in adult controlled trials and long-term open-label studies, with < 1% of patients discontinuing due to sleepwalking. Rates of sleepwalking were similar for patients taking placebo and patients taking sodium oxybate oral solution in controlled trials. It is unclear if some or all of the reported sleepwalking episodes correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific medical disorder. Five instances of sleepwalking with potential injury or significant injury were reported during a clinical trial of sodium oxybate oral solution in patients with narcolepsy. Parasomnias, including sleepwalking, also have been reported in postmarketing experience with sodium oxybate oral solution. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered. Pediatric use information is approved for Jazz Pharmaceuticals Inc.’s XYREM (sodium oxybate) Oral Solution. However, due to Jazz Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 5.8 Use in Patients Sensitive to High Sodium Intake Sodium oxybate oral solution has a high salt content. In patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose of sodium oxybate oral solution. Table 3 provides the approximate sodium content per sodium oxybate oral solution dose. Table 3 Approximate Sodium Content per Total Nightly Dose of Sodium oxybate oral solution (g = grams) Sodium oxybate oral solution Dose Sodium Content/Total Nightly Exposure 3 g per night 550 mg 4.5 g per night 820 mg 6 g per night 1100 mg 7.5 g per night 1400 mg 9 g per night 1640 mg

7 DRUG INTERACTIONS Concomitant use with divalproex sodium: An initial reduction in sodium oxybate oral solution dose of at least 20% is recommended (2.5, 7.2). 7.1 Alcohol, Sedative Hypnotics, and CNS Depressants Sodium oxybate oral solution is contraindicated for use in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of sodium oxybate oral solution [see Warnings and Precautions (5.1)]. 7.2 Divalproex Sodium Concomitant use of sodium oxybate oral solution with divalproex sodium results in an increase in systemic exposure to GHB, which was shown to cause a greater impairment on some tests of attention and working memory in a clinical study [see Clinical Pharmacology (12.3)]. An initial dose reduction of sodium oxybate oral solution is recommended when used concomitantly with divalproex sodium [see Dosage and Administration (2.5)]. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of sodium oxybate oral solution and divalproex sodium is warranted.

6 ADVERSE REACTIONS The following clinically significant adverse reactions appear in other sections of the labeling: CNS depression [see Warnings and Precautions (5.1)] Abuse and Misuse [see Warnings and Precautions (5.2)] Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions (5.4)] Depression and Suicidality [see Warnings and Precautions (5.5)] Other Behavioral or Psychiatric Adverse Reactions [see Warnings and Precautions (5.6)] Parasomnias [see Warnings and Precautions (5.7)] Use in Patients Sensitive to High Sodium Intake [see Warnings and Precautions (5.8)] Most common adverse reactions in adults (≥5% and at least twice the incidence with placebo) were nausea, dizziness, vomiting, somnolence, enuresis, and tremor (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Camber Pharmaceuticals, Inc. at 1-866-495-8330, or FDA at 1-800-FDA-1088 or www.fda.gov/Medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adult Patients Sodium oxybate oral solution was studied in three placebo-controlled clinical trials (Trials N1, N3, and N4, described in Sections 14.1 and 14.2) in 611 patients with narcolepsy (398 subjects treated with sodium oxybate oral solution, and 213 with placebo). A total of 781 patients with narcolepsy were treated with sodium oxybate oral solution in controlled and uncontrolled clinical trials. Section 6.1 and Table 4 present adverse reactions from three pooled, controlled trials (N1, N3, N4) in patients with narcolepsy. Adverse Reactions Leading to Treatment Discontinuation: Of the 398 patients with narcolepsy treated with sodium oxybate oral solution, 10.3% of patients discontinued because of adverse reactions compared with 2.8% of patients receiving placebo. The most common adverse reaction leading to discontinuation was nausea (2.8%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment. Commonly Observed Adverse Reactions in Controlled Clinical Trials: The most common adverse reactions (incidence ≥5% and twice the rate seen with placebo) in patients treated with sodium oxybate oral solution were nausea, dizziness, vomiting, somnolence, enuresis, and tremor. Adverse Reactions Occurring at an Incidence of 2% or Greater: Table 4 lists adverse reactions that occurred at a frequency of 2% or more in any treatment group for three controlled trials and were more frequent in any sodium oxybate oral solution treatment group than with placebo. Adverse reactions are summarized by dose at onset. Nearly all patients in these studies initiated treatment at 4.5 g per night. In patients who remained on treatment, adverse reactions tended to occur early and to diminish over time. Table 4 Adverse Reactions Occurring in ≥2% of Adult Patients and More Frequently with Sodium oxybate oral solution than Placebo in Three Controlled Trials (N1, N3, N4) by Body System and Dose at Onset Adverse Reaction Placebo (n=213) % Sodium oxybate oral solution 4.5g (n=185) % Sodium oxybate oral solution 6g (n=258) % Sodium oxybate oral solution 9g (n=178) % ANY ADVERSE REACTION 62 45 55 70 GASTROINTESTINAL DISORDERS Nausea 3 8 13 20 Vomiting 1 2 4 11 Diarrhea 2 4 3 4 Abdominal pain upper 2 3 1 2 Dry mouth 2 1 2 1 GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Pain 1 1 <1 3 Feeling drunk 1 0 <1 3 Edema peripheral 1 3 0 0 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Cataplexy 1 1 1 2 Muscle spasms 2 2 <1 2 Pain in extremity 1 3 1 1 NERVOUS SYSTEM DISORDERS Dizziness 4 9 11 15 Somnolence 4 1 3 8 Tremor 0 0 2 5 Disturbance in attention 0 1 0 4 Paresthesia 1 2 1 3 Sleep paralysis 1 0 1 3 PSYCHIATRIC DISORDERS Disorientation 1 1 2 3 Irritability 1 0 <1 3 Sleepwalking 0 0 0 3 Anxiety 1 1 1 2 RENAL AND URINARY DISORDERS Enuresis 1 3 3 7 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Hyperhidrosis 0 1 1 3 Dose-Response Information In clinical trials in narcolepsy, a dose-response relationship was observed for nausea, vomiting, paresthesia, disorientation, irritability, disturbance in attention, feeling drunk, sleepwalking, and enuresis. The incidence of all these reactions was notably higher at 9 g per night. In controlled trials in narcolepsy, discontinuations of treatment due to adverse reactions were greater at higher doses of sodium oxybate oral solution. Pediatric use information is approved for Jazz Pharmaceuticals Inc.’s XYREM (sodium oxybate) Oral Solution. However, due to Jazz Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sodium oxybate oral solution. 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 drug exposure: arthralgia, decreased appetite, fall*, fluid retention, hangover, headache, hypersensitivity, hypertension, memory impairment, nocturia, panic attack, vision blurred, and weight decreased. *The sudden onset of sleep in patients taking sodium oxybate, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of sodium oxybate in pregnant women. Oral administration of sodium oxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity; however, oral administration to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and growth, at a clinically relevant dose [see Data] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Labor or Delivery Sodium oxybate oral solution has not been studied in labor or delivery. In obstetric anesthesia using an injectable formulation of sodium oxybate, newborns had stable cardiovascular and respiratory measures but were very sleepy, causing a slight decrease in Apgar scores. There was a fall in the rate of uterine contractions 20 minutes after injection. Placental transfer is rapid and gamma-hydroxybutyrate (GHB) has been detected in newborns at delivery after intravenous administration of GHB to mothers. Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown. Data Animal Data Oral administration of sodium oxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity. The highest doses tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m 2 ) basis. Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and body weight gain at the highest dose tested. The no-effect dose for pre- and post­natal developmental toxicity in rats is less than the MRHD on a mg/m 2 basis.