Methylnaltrexone

In patients with severe renal impairment (creatinine clearance less than 30 mL/min), the dose of methylnaltrexone bromide should be reduced from 12 mg to 8 mg (0.4 mL of solution) for those weighing 62 to 114 kg. Patients with severe renal impairment whose weight falls outside the 62 to 114 kg range need to reduce their mg/kg dose by 50%. There are no data available from patients with end-stage renal impairment on dialysis, and methylnaltrexone bromide is not recommended in these patients.

There are no data available from patients with severe hepatic impairment (Child-Pugh Class C), and methylnaltrexone bromide is not recommended in these patients.

The organic cation transporter (OCT)-related drug-drug interaction potential between methylnaltrexone bromide and an OCT inhibitor was studied in 18 healthy subjects by comparing the single-dose pharmacokinetic profiles of methylnaltrexone bromide before and after multiple 400 mg doses of cimetidine. The renal clearance of methylnaltrexone bromide was reduced following multiple-dose administration of cimetidine (from 31 L/h to 18 L/h). However, this resulted in a small reduction in total clearance (from 107 L/h to 95 L/h). Consequently, no meaningful change in AUC of methylnaltrexone bromide, in addition to C_max, was observed before and after multiple-dose administration of cimetidine.

Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, vomiting, abdominal pain, palpitations, and blushing have occurred in patients treated with methylnaltrexone bromide. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. This should be taken into account when prescribing methylnaltrexone bromide for such patients.

There are no adequate data with the use of methylnaltrexone bromide in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Methylnaltrexone bromide should not be used during pregnancy unless clearly necessary.

It is unknown whether methylnaltrexone bromide is excreted in human breast milk. Animal studies have shown excretion of methylnaltrexone bromide in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with methylnaltrexone bromide should be made, taking into account the benefit of breast-feeding to the child and the benefit of methylnaltrexone bromide therapy to the woman.

Fertility

Subcutaneous injections of methylnaltrexone bromide at 150 mg/kg/day decreased fertility in rats. Doses up to 25 mg/kg/day (18 times the exposure [AUC] in humans at a subcutaneous dose of 0.3 mg/kg) did not affect fertility or general reproductive performance.

Methylnaltrexone bromide has minor influence on the ability to drive and use machines. Dizziness may occur and this may have an effect on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions in all patients exposed to methylnaltrexone bromide during all phases of placebo-controlled studies were abdominal pain, nausea, diarrhoea and flatulence. Generally, these reactions were mild or moderate.

List of adverse reactions

The adverse reactions are classified as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Nervous system disorders

Common: Dizziness

Common: opioid-withdrawal-like symptoms (like chills, tremor, rhinorrhea, piloerection, hot flush, palpitation, hyperhidrosis, vomiting, abdominal pain)

Gastrointestinal disorders

Not known: Gastrointestinal perforation

Common: Vomiting

Very common: Abdominal pain, nausea, diarrhoea, flatulence

Skin and subcutaneous tissue disorders

Common: Injection site reactions (e.g. stinging, burning, pain, redness, oedema)