What is the safety data for methocarbamol (Robaxin) IV in renally impaired patients due to PEG toxicity? How real or how often does this occur? Can this be reduced by lowering the dose?

Every time I verify Robaxin IV orders, EPIC tells me to watch out in renally impaired patients due to PEG toxicity. How real or how often does this occur? Can this be reduced by lowering the dose?

Comment by InpharmD Researcher

Although methocarbamol appears to be relatively safe in patients with renal impairment, the intravenous formulation is contraindicated in patients with renal insufficiency due to the presence of polyethylene glycol 300 in the vehicle. Even though the amount of polyethylene glycol present in this preparation is well within the limits of safety, this contraindication exists due to the possibility of acidosis and nephrotoxicity observed when polyethylene glycol is administered in high concentrations as an excipient of other medications. Yet due to an overall lack of data, including evidence on whether lower doses lessen the risk, the safety of deviating from the recommendations remains unknown, and patients should be consistently monitored for signs of toxicity if administered a dose.

Background

A 2024 commentary examines the debated topic of polyethylene glycol (PEG) toxicity associated with intravenous methocarbamol. The commentary delves into the potential risks and evidence concerning PEG-related metabolic acidosis and nephrotoxicity, particularly in patients with renal dysfunction. Intravenous methocarbamol, widely prescribed as an antispasmodic muscle relaxant, contains PEG as an excipient, which has been implicated in adverse events in patients with compromised renal function. This publication brings to light that, despite the presence of such warnings in prescribing information, there is a marked absence of case reports or observational studies substantiating these adverse outcomes. The authors explore both sides of the argument by presenting past findings of PEG toxicity in other medications, yet highlighting the lack of concrete evidence specifically linking PEG in intravenous methocarbamol to clinical toxicity. Included in the discussion are comparisons with other PEG-containing products, which have documented toxic effects in specific scenarios, yet the commentary emphasizes that methocarbamol's relatively low PEG content may not reach harmful levels in most patients. The authors call for further investigation and data to more accurately define the risk profile and monitoring parameters, indicating that current evidence does not sufficiently support clinical manifestations of PEG toxicity from intravenous methocarbamol. [1]

Relevant Prescribing Information

Special Populations [2]
Renally Impaired

The clearance of methocarbamol in 8 renally-impaired patients on maintenance hemodialysis was reduced about 40% compared to 17 normal subjects, although the mean (± SD) elimination half-life in these two groups was similar (1.2 (± 0.6) versus 1.1 (± 0.3) hours, respectively).

Contraindications:
Methocarbamol Injection should not be administered to patients with known or suspected renal pathology. This caution is necessary because of the presence of polyethylene glycol 300 in the vehicle. A much larger amount of polyethylene glycol 300 than is present in recommended doses of Methocarbamol Injection is known to have increased pre-existing acidosis and urea retention in patients with renal impairment. Although the amount present in this preparation is well within the limits of safety, caution dictates this contraindication.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Every time I verify Robaxin IV orders, EPIC tells me to watch out in renally impaired patients due to PEG toxicity. How real or how often does this occur? Can this be reduced by lowering the dose?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-2 for your response.

Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals
Design	Pharmacokinetic study N= 25
Objective	To assess the pharmacokinetics of a single oral methocarbamol 1,500 mg dose in both normal subjects and patients undergoing maintenance hemodialysis
Study Groups	Hemodialysis (n= 8) Healthy controls (n= 17)
Inclusion criteria	Patients with renal failure undergoing maintenance hemodialysis
Exclusion criteria	Any laboratory abnormalities other than those accompanying renal failure
Methods	Participants were given a single 1.5 g dose of oral methocarbamol on their off-dialysis day. Samples were collected for up to 24 hours.
Duration	24 hours
Outcome Measures	Maximum concentration (C_max), time to maximum concentration (t_max), area under the curve of drug concentration in blood plasma versus time (AUC), half-life (t_1/2)
Baseline Characteristics	The renal failure population consisted of six males and two females and their average age was 32 ± 6.8years. No baseline information for the controls was reported.
Results		Hemodialysis (n= 8)	Control (n= 17)
	Weight, kg	68.7 ± 14.1	78.6 ± 8.1
	t_max, hours	1.1 ± 0.6	1.1 ± 0.6
	C_max, mg/L	28.7 ± 8.8	21.3 ± 8.2
	AUC, mg*h/L	87.1 ± 54.8	52.5 ± 23.7
	t_1/2, hours	1.24	1.14
Adverse Events	N/A
Study Author Conclusions	These data suggest that the absorption and elimination of methocarbamol is similar between normal subjects and patients undergoing maintenance hemodialysis.

References:

Sica DA, Comstock TJ, Davis J, et al. Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals. Eur J Clin Pharmacol. 1990;39(2):193-4.

Polyethylene glycol nephrotoxicity secondary to prolonged high-dose intravenous lorazepam
Study Design	Case report
Case Presentation	A 57-year-old man with a history of alcohol abuse was admitted to the pulmonary ICU for acute respiratory failure, hypoxemia, metabolic acidosis, and probable community-acquired pneumonia. His serum creatinine was 71 µmol/L. He was intubated, started on mechanical ventilation, and given empiric IV erythromycin and ampicillin-sulbactam. Lorazepam (1-2 mg IV q4h) was initiated to prevent alcohol withdrawal. By day 2, morphine was added, and lorazepam was increased to 4 mg/h via continuous infusion. On day 5, a chest X-ray showed diffuse lung infiltrates consistent with ARDS. By day 10, the patient was struggling against the ventilator, and by day 12, despite high doses of lorazepam (18 mg/h), haloperidol, morphine, and pancuronium, he continued to fight ventilation. To reduce lorazepam use (due to cost and limited efficacy), morphine and pancuronium were increased to 4 mg/h, and lorazepam was tapered to an average of 10 mg/h over the next week. By day 17, his BUN rose to 16 mmol/L, while creatinine remained stable at 80 µmol/L. By day 43, lorazepam was reduced to 3 mg IV q6h, but BUN increased to 26 mmol/L, and creatinine nearly doubled to 124 µmol/L within 24 hours. Nephrology consultation suggested acute tubular necrosis (ATN) of unknown cause. Hemodialysis was initiated three times weekly as renal function worsened. Over the next two weeks, his renal function improved, and he was discharged home after full recovery.
Author's Conclusions	Patients who are administered usual therapeutic dosages of intravenous lorazepam receive only trace amounts of polyethylene glycol (PEG) 400 via the diluent. This patient, however, received a cumulative intravenous lorazepam dose of 4089 mg, which averages about 95 mg/d over 43 days. The corresponding cumulative PEG 400 dose was about 220 mL administered before the onset of ATN.

References:

Laine GA, Hossain SM, Solis RT, Adams SC. Polyethylene glycol nephrotoxicity secondary to prolonged high-dose intravenous lorazepam. Ann Pharmacother. 1995;29(11):1110-4.