Methenamine 1 g

Topical methenamine is indicated for the treatment and prevention of plantar hyperhidrosis and associated malodour, and as adjunct in the treatment of athlete’s foot when excessive perspiration contributes to worsening of the condition. Topical methenamine has been shown to be effective in the treatment of palmoplantar hyperhidrosis in adults.

Methenamine can cause suppression or elimination of bacteriuria, and is therefore used primarily for the prevention rather than treatment of upper and lower urinary tract infections (UTIs). Oral methenamine is approved for the suppression or elimination of bacteriuria associated with pyelonephritis, cystitis and other urinary tract infections. Methenamine is not effective in the treatment of pyelonephritis. It is not used to treat infections outside the urinary tract, because it remains inactive until it is excreted by the kidneys into the urinary tract where formaldehyde is produced and concentrates in the bladder.

Despite many studies in various subgroups of patients, the data on efficacy are not strong largely due to poor quality studies with contradictory results. Compared to placebo, oral methenamine appears effective in preventing either bacteriuria or symptomatic UTIs in young, otherwise healthy people when other antimicrobial agents have not been effective. Oral methenamine has been used for the prevention of recurrent symptomatic UTIs in children when intermittent catheterization techniques used in urinary bladder voiding dysfunction or when other antibiotics have not been effective. Methenamine has been used as short-term prophylaxis (≤7 days) in patients without renal abnormalities, such as women undergoing short-term bladder catheterization, to decrease the incidence of symptomatic UTI; however, effective alternatives such as other oral antibacterial agents should be considered first. Using methenamine in men with chronic bacteriuria resulted in reduced recurrence and fewer acute exacerbations of UTI but superiority to other oral antibacterials has not been demonstrated. Oral methenamine is not effective in preventing UTIs in patients with indwelling bladder catheters as sufficient concentrations of formaldehyde cannot be generated in this clinical setting.

Oral methenamine is not used for the treatment of acute UTIs. Though oral methenamine is approved in patients with neurologic diseases leading to an infected residual urine, in one study, benefit in terms of UTI prevention was not seen in spinal cord–injured patients with neurogenic bladder. Overall, methenamine has not shown to be superior to other antibacterials in the suppression and prevention of urinary tract infections. Oral methenamine should be considered as an alternative to other antibacterial agents in cases of intolerance, allergy, treatment failure or resistance.

Formaldehyde generation from methenamine is dependent on acidic urinary pH; avoid methenamine in patients who are unable to achieve and maintain an acidic urinary pH, e.g., patients with a more alkaline pH (pH >5.5) due to their diet. Using vitamin C or other acidifying agents has not been demonstrated to improve the effectiveness of methenamine, but the effect on urinary pH can be monitored; weigh possible benefits against the unlikely risks associated with these agents. Treatment failures may also be due to urease-producing bacteria in urine such as Proteus and Pseudomonas as methenamine conversion to formaldehyde is prevented by the resulting alkaline urine.

Evidence for the therapeutic use of the effervescent form of methenamine is limited.

Clinical studies of methenamine did not include significant numbers of subjects over 65 years of age. No differences in toxicity have been observed in older individuals when compared to other age groups. Because of age-related declines in kidney and liver functions, initiate therapy in older individuals at the lower end of the dose range.

Pregnancy Category C_M. Use of methenamine during pregnancy has not been adequately studied. It is unknown whether methenamine crosses the placenta. Studies in rats, rabbits and dogs have found little or no evidence of fetal harm. Limited human data does not support a greater incidence of congenital defects relative to the baseline risk. The use of methenamine during pregnancy requires the potential benefits be weighed against the possible risks to the mother and the fetus.

Methenamine is excreted in small amounts in the breast milk, peaking at 1 hour after ingestion. No adverse effects have been reported in nursing infants. The use of methenamine during nursing requires that potential benefits be weighed against the possible risks to the mother and infant.

Monitor liver enzymes periodically in patients with pre-existing liver insufficiency. Prior to initiation of therapy, perform urinalysis and/or cultures. Monitor for clinical signs and symptoms of a urinary tract infection.

The volume of distribution of methenamine is 0.56 L/kg. It is unknown whether methenamine crosses the placenta. Methenamine enters into the breast milk where it achieves concentrations similar to that found in the serum. Mandelic acid also enters breast milk.

Methenamine is readily absorbed following oral administration. Approximately 82 to 88% of the administered dose is recovered in the urine of healthy volunteers in a 24-hour period. Approximately 10 to 30% of the methenamine dose is hydrolyzed to ammonia and formaldehyde in the acidic environment of the stomach.

Oral methenamine has no systemic antibacterial effects. Methenamine remains inactive until it is excreted by the kidneys into the lower urinary tract. Formaldehyde is produced through hydrolysis of methenamine in acidic urine, and concentrates in the bladder. Urinary pH is an important factor in determining the effectiveness of methenamine due to the amount of formaldehyde liberated. At a pH of 7.4, there is almost no formaldehyde produced; a 6% yield (of the theoretical amount) occurs at a pH of 6 and 20% at a pH of 5. When administered as the mandelate salt, mandelic acid helps to acidify the urine and fosters a bacteriostatic environment by promoting the conversion of methenamine to formaldehyde; a pH of <5 is reached in the stomach, urine and sweat.

Effectiveness of methenamine is influenced not only by the rate of formaldehyde generation but also by the duration of exposure of bacteria to formaldehyde. With methenamine concentrations of 1000 µg/mL, more than 6 h is needed to generate a formaldehyde concentration >25 µg/mL at pH 6.5 and approximately 3 hours at pH 5.85. Approximately 2 hours is needed at this concentration for antibacterial activity. Patients who void frequently or who have their bladders drained frequently may not benefit from methenamine treatment as such actions reduce exposure time of bacteria to formaldehyde and reduce formaldehyde concentrations in the urine.

Almost all bacteria are susceptible to free urine formaldehyde concentration of ≥20 µg/mL. Acquired resistance is deemed unlikely to develop with methenamine; the antibacterial action of methenamine involves non-specific mechanisms and can therefore be used long-term. Formaldehyde is equally effective against Gram-positive and Gram-negative microorganisms, and fungi.

Topical methenamine is hydrolyzed to formaldehyde in sweat. Relief of hyperhidrosis is achieved by decreasing the solubility of protein through a direct interaction between formaldehyde and polypeptides which results in the blockage of affected sweat ducts.

Methenamine is renally cleared. Approximately 70 to 90% of methenamine is excreted unchanged through glomerular filtration and tubular excretion. The half-life of methenamine is around 4 hours. Bactericidal formaldehyde concentrations in the urine are not achieved until methenamine reaches the bladder.