Version July 2025
Oxybate salts (calcium, magnesium, potassium, and sodium) are CNS depressants. Clinically significant respiratory depression and obtundation may occur in patients treated with oxybate salts (calcium, magnesium, potassium, and sodium) at recommended doses. Many patients who received oxybate salts (calcium, magnesium, potassium, and sodium) during clinical trials in narcolepsy and idiopathic hypersomnia were receiving CNS stimulants.
The active moiety of oxybate salts (calcium, magnesium, potassium, and sodium) is oxybate or gamma-hydroxybutyrate (GHB). Abuse or misuse 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.
Because of the risks of CNS depression and abuse and misuse, oxybate salts (calcium, magnesium, potassium, and sodium) is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XYWAV and XYREM REMS.
Hypersomnia (idiopathic):
Once-nightly dosing: Initial: Oral: ≤3 g at bedtime after the patient is in bed. May increase nightly dose by ≤1.5 g at weekly intervals based on efficacy and tolerability; maximum dose: 6 g/night.
Twice-nightly dosing: Initial: Oral: ≤2.25 g at bedtime after the patient is in bed and ≤2.25 g taken 2.5 to 4 hours later (≤4.5 g/night). May increase nightly dose by ≤1.5 g (≤0.75 g at bedtime and ≤0.75 g 2.5 to 4 hours later) at weekly intervals based on efficacy and tolerability; maximum dose: 9 g/night. Note: Some patients may achieve better responses with unequal nightly doses at bedtime and 2.5 to 4 hours later.
Narcolepsy: Oral: Initial: 2.25 g at bedtime after the patient is in bed, and 2.25 g taken 2.5 to 4 hours later (4.5 g/night). May increase nightly dose by 1.5 g (0.75 g at bedtime and 0.75 g 2.5 to 4 hours later) at weekly intervals based on efficacy and tolerability; usual effective dosage range: 6 to 9 g/night. Maximum dose: 9 g/night.
Missed second dose: Skip dose and resume usual dosing schedule the next day. Do not administer 2 doses at the same time.
Conversion from sodium oxybate to oxybate salts (calcium, magnesium, potassium, and sodium): On the first night of dosing with oxybate salts (calcium, magnesium, potassium, and sodium), initiate treatment at the same dose (gram for gram) and regimen as sodium oxybate.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, not renally eliminated.
Reduce initial dose by 50%.
Refer to adult dosing; use with caution.
(For additional information see "Mixed-salt oxybate (gamma hydroxybutyrate): Pediatric drug information")
Narcolepsy (excessive daytime sleepiness/cataplexy): Note: Nightly, 2 doses are administered; some patients may require unequal doses to achieve optimal response. Dosing is presented as grams of oxybate.
Children ≥7 years and Adolescents:
<20 kg: Oral: There are no specific dosage recommendations in the manufacturer's labeling due to insufficient data; however, a lower initial starting dose and lower maximum dosages are recommended.
20 to <30 kg: Oral: Initial: ≤1 g at bedtime after the patient is in bed, then 2.5 to 4 hours later, administer second dose of ≤1 g. After 1 week, titrate dose based on efficacy and tolerability at weekly intervals; increase dose in ≤0.5 g/dose (≤1 g/night) increments per week; maximum single dose: 3 g/dose; maximum daily dose: 6 g/night.
30 to <45 kg: Oral: Initial: ≤1.5 g at bedtime after the patient is in bed, then 2.5 to 4 hours later, administer second dose of ≤1.5 g. After 1 week, titrate dose based on efficacy and tolerability at weekly intervals; increase dose in ≤0.5 g/dose (≤1 g/night) increments per week; maximum single dose: 3.75 g/dose; maximum daily dose: 7.5 g/ night.
≥45 kg: Oral: Initial: ≤2.25 g at bedtime after the patient is in bed, then 2.5 to 4 hours later, administer second dose of ≤2.25 g . After 1 week, titrate dose based on efficacy and tolerability at weekly intervals; increase dose in ≤0.75 g/dose (≤1.5 g/night) increments per week; maximum single dose: 4.5 g/dose; maximum daily dose: 9 g/night.
Converting from sodium oxybate (Xyrem) to oxybate salts (calcium, magnesium, potassium, and sodium oxybate) (Xywav): Discontinue sodium oxybate (Xyrem) and initiate oxybate salts (calcium, magnesium, potassium, and sodium) (Xywav) at the same dose (gram per gram); titrate as needed based on efficacy and tolerability.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Children ≥7 years and Adolescents: Reduce initial total nightly dose by 50% and administer in 2 divided doses.
Use of oxybate salts was associated with neuropsychiatric effects in adult and pediatric patients during clinical trials, including agitation, anxiety, confusion, irritability, panic attack, tension, and visual hallucinations; aggression, paranoia, and psychosis have also been reported with sodium oxybate (which has the same active moiety as oxybate salts).
Treatment discontinuation has been reported in patients who experienced neuropsychiatric effects.
Clinically significant central nervous system (CNS) depression, respiratory depression, and obtundation may occur in adult and pediatric patients, even at recommended doses. Increased apnea (including sleep-related apnea) and clinically relevant reduced oxygenation may also occur. CNS and respiratory depression are reversible following dosage modification, interruption of therapy, and/or discontinuation.
Mechanism: Dose-related (Teter 2001); related to the pharmacologic action (ie, GABAB receptor activity)
Onset: Rapid
Risk factors:
• Concomitant use with other CNS depressants (eg, opioids, benzodiazepines, sedating antidepressants/antipsychotics/antiseizure medications, general anesthetics, muscle relaxants, illicit CNS depressants); associated with an increased risk of respiratory depression, hypotension, profound sedation, syncope, and death. Note: Use of oxybate salts is contraindicated with alcohol and sedative hypnotics.
• Impaired respiratory drive:
- Preexisting compromised respiratory function
• Sleep-related breathing disorders:
- Obesity
- Male patients
- Female patients who are postmenopausal and not on hormone-replacement therapy
- Patients with narcolepsy
Parasomnias, including abnormal dreams, night terrors, sleep paralysis, sleep talking, and somnambulism, have been reported in both adult and pediatric patients during clinical trials. Parasomnias have led to treatment discontinuation.
Treatment with oxybate salts was associated with an increased incidence of depression (including depressed mood), suicidal ideation, and suicidal tendencies in both adult and pediatric patients during clinical trials. Treatment discontinuation secondary to depression was also reported.
Risk factors:
• Prior history of depression and/or suicide attempt
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Gastrointestinal: Nausea (13%)
Nervous system: Headache (20%)
1% to 10%:
Dermatologic: Diaphoresis (including night sweats: 6%)
Gastrointestinal: Decreased appetite (8%), diarrhea (6%), vomiting (5%), xerostomia (4%)
Genitourinary: Urinary incontinence (4%)
Nervous system: Anxiety (including agitation, panic attack, and tension: 5%), confusion (1%), depressed mood (4%), depression (3%), dizziness (10%), drowsiness (2%), fatigue (including asthenia: 4%), irritability (3%), parasomnias (including abnormal dreams, night terrors, sleep paralysis, sleep talking, and somnambulism with a potential for injury: 6%), paresthesia (3%)
Neuromuscular & skeletal: Muscle spasm (2%), tremor (3%)
<1%: Nervous system: Visual hallucination
Frequency not defined:
Nervous system: Central nervous system depression, obtundation, suicidal ideation, suicidal tendencies
Respiratory: Respiratory depression
Concomitant use with sedative hypnotics or alcohol; succinic semialdehyde dehydrogenase deficiency.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to oxybate salts (calcium, magnesium, potassium, and sodium) or any component of the formulation.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Disease-related concerns:
• Hepatic insufficiency: Use with caution in patients with preexisting liver impairment.
Other warnings/precautions:
• Tolerance/withdrawal: Tolerance to oxybate salts (calcium, magnesium, potassium, and sodium), or withdrawal following its discontinuation, has not been clearly defined in controlled clinical trials, but has been reported at larger doses used for illicit purposes.
Each mL contains 0.5 g of oxybate salts present as 0.234 g calcium oxybate, 0.096 g magnesium oxybate, 0.13 g potassium oxybate, and 0.04 g sodium oxybate.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral:
Xywav: 500 mg/mL (180 mL) [barley free, gluten free, rye free, wheat free]
No
Solution (Xywav Oral)
500 mg/mL (per mL): $43.93
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral:
Xywav: 500 mg/mL (180 mL)
C-I (illicit use); C-III (medical use)
Canada: Available through a controlled distribution program. Registration with the program is required for participating prescribers and pharmacists. Patients must also be registered with the program and meet all necessary requirements to receive oxybate salts. For further information, call 1-866-599-7365 or write to [email protected].
Oral: Administer on an empty stomach, ≥2 hours after eating. Administer dose at bedtime. For patients taking a second nightly dose, administer second dose 2.5 to 4 hours after the first dose; an alarm clock may need to be set for the second dose. Prepare both doses prior to bedtime. Prior to ingestion, dilute each dose with approximately ¼ cup water in provided empty pharmacy containers. Administer both doses while patient is in bed; patient should lie down immediately after dose and remain in bed.
Oral: Administer on an empty stomach (at least 2 hours after eating); administration at similar times each night is preferred. Each nightly dose should be administered while patient is sitting up in bed, then patient should immediately lie down and remain in bed; sleep generally occurs within 5 to 15 minutes (generally abruptly without patient feeling drowsy). Both doses should be prepared prior to bedtime. The first dose is administered at bedtime and the second dose is administered 2.5 to 4 hours later; an alarm clock may need to be set for the second dose. For patients who sleep >8 hours per night the first dose may be administered at bedtime or after an initial period of sleep. After use, rinse containers with water.
Missed dose: If the second dose is missed, skip that dose and resume therapy the next night; do not administer both doses at the same time. Diluted doses that are not used should be properly and promptly disposed.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212690s011lbl.pdf#page=29, must be dispensed with this medication.
Hypersomnia (idiopathic): Treatment of idiopathic hypersomnia in adults.
Narcolepsy: Treatment of cataplexy or excessive daytime sleepiness in patients ≥7 years of age with narcolepsy.
Oxybate salts (calcium, magnesium, potassium, and sodium) may be confused with sodium oxybate.
Xywav may be confused with Xyrem.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May increase CNS depressant effects of Oxybate Salt Products. Alcohol (Ethyl) may increase serum concentration of Oxybate Salt Products. Specifically, alcohol may increase concentrations of the sodium oxybate extended release suspension. Risk X: Avoid
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Barbiturates: May increase CNS depressant effects of Oxybate Salt Products. Risk X: Avoid
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Benzodiazepines: May increase CNS depressant effects of Oxybate Salt Products. Risk X: Avoid
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
CNS Depressants: May increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Hypnotics (Nonbenzodiazepine): May increase CNS depressant effects of Oxybate Salt Products. Risk X: Avoid
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Rilmenidine: Oxybate Salt Products may increase CNS depressant effects of Rilmenidine. Risk X: Avoid
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valproic Acid and Derivatives: May increase serum concentration of Oxybate Salts (Calcium, Magnesium, Potassium, and Sodium). Management: Decrease the dose of oxybate salts by at least 20% when initiating therapy with valproate products. When initiating oxybate salts in patients taking valproate products, use a lower starting dose of oxybate salts. Risk D: Consider Therapy Modification
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Administration of oxybate salts (calcium, magnesium, potassium, and sodium) immediately following a high-fat meal decreases gamma-hydroxybutyrate Cmax by 33% and AUC by 16%. Management: Administer first nightly dose at least 2 hours after eating.
The active moiety of oxybate salts, gamma-hydroxybutyrate, crosses the placenta. The injection formulation of sodium oxybate, when used as an anesthetic during labor and delivery, was shown to cause a slight decrease in Apgar scores due to sleepiness in the neonate.
The active moiety of oxybate salts, gamma-hydroxybutyrate, is present in breast milk following oral administration of sodium oxybate.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Emergent or worsening depression, suicidal ideation, emergence or increase in the occurrence of behavioral or psychiatric events; impaired motor/cognitive function; signs of drug abuse, misuse, substance use disorder, or diversion.
The active moiety of oxybate salts (calcium, magnesium, potassium, and sodium) is oxybate or gamma-hydroxybutyrate (GHB). The therapeutic effects of GHB, a metabolite of GABA, are hypothesized to be mediated by GABAB receptor activity at noradrenergic, dopaminergic, and thalamocortical neurons.
Onset: Rapid (≤5 to 15 minutes).
Distribution: Vd: 190 to 384 mL/kg.
Protein binding: <1%.
Metabolism: Primarily via the Krebs cycle to form water and carbon dioxide; secondarily via beta oxidation; no active metabolites.
Half-life elimination: ~0.66 hours.
Time to peak: ~1.3 hours.
Excretion: Primarily via biotransformation to carbon dioxide and expiration; Urine: <5% as unchanged drug.
Hepatic function: AUC is doubled, elimination half-life is longer, and oral clearance is reduced in cirrhotic patients (Child-Pugh class A and C).
