Methenamine

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not indicated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: public available literature (non GLP, on Guideline)

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

The Pharmacological Basis of Therapeutics.

Author:

Goodman, L.S., Gilman, A.

Year:

1975

Bibliographic source:

5th ed., MacMillan, New York 1975, 1006-1007

Reference 2

Reference Type:

publication

Title:

The Complete Drug Reference.

Author:

Martindale

Year:

2005

Bibliographic source:

Ed. Sean C. Sweetman, Pharmaceutical Press London, 34th Edition, 230

Materials and methods

Study type:

clinical case study

Endpoint addressed:

repeated dose toxicity: oral

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Public avaialble literature. No guideline indicated. For details on method see materials and methods section.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Methenamine

EC Number:

202-905-8

EC Name:

Methenamine

Cas Number:

100-97-0

Molecular formula:

C6H12N4

IUPAC Name:

1,3,5,7-tetraazatricyclo[3.3.1.1³,⁷]decane

Test material form:

solid: crystalline

Method

Type of population:

general

Subjects:

general population (Methenamine used as drug).

Ethical approval:

not specified

Route of exposure:

oral

Reason of exposure:

intentional

Exposure assessment:

not specified

Details on exposure:

- high therapeutic doses of 8 g methenamine/d (corresponding to ca. 114 mg/kg bw/d based on a body weight of 70) administered for 3 to 4 weeks.
- dose levels of 2 to 4 g/d (corresponding to about 28 to 57 mg/kg bw/d based on a body weight of 70 kg) for a 7- to 10-day course up to four weeks.

Examinations:

general health parameters.

Medical treatment:

Methenamine and its salts were used as drug.

Results and discussion

Clinical signs:

High therapeutic doses of 8 g methenamine/d (corresponding to ca. 114 mg/kg bw/d based on a body weight of 70) administered for 3 to 4 weeks induced urological abnormalities such as bladder irritation, painful and frequent micturition, albuminuria and hematuria. Singular side effects reported were gingivitis, anorexia, headache, and generalized edema.
No complications were observed in patients receiving methenamine in the standard treatment for acute cystitis in adults at dose levels of 2 to 4 g/d (corresponding to about 28 to 57 mg/kg bw/d based on a body weight of 70 kg) for a 7- to 10-day course up to four weeks. Methenamine is also used for long-term suppressive therapy or for prevention of recurrent urinary infections (prophylaxis) because acquired resistance does not appear to develop. The usual oral dose of methenamine (methenamine hippurate or methenamine mandelate) for long-term treatment (6 months or longer) is 2-4 x 1 g/d (corresponding to ca. 28-57 mg/kg bw/d based on a body weight of 70 kg) No relevant side effects from the treatment with this dose level were reported.

Results of examinations:

see clinical signs.

Effectivity of medical treatment:

Methenamine is used as drug (effective use).

Outcome of incidence:

not applicable.

Applicant's summary and conclusion

Conclusions:

A NOAEL of 4 g/d (57 mg/kg bw/d based on a body weight of 70 kg person) methenamine in man is derived from decades of long experience with methenamine as a therapeutic substance.

Executive summary:

High therapeutic doses of 8 g methenamine/d (corresponding to ca. 114 mg/kg bw/d based on a body weight of 70) administered for 3 to 4 weeks induced urological abnormalities such as bladder irritation, painful and frequent micturition, albuminuria and hematuria. Singular side effects reported were gingivitis, anorexia, headache, and generalized edema.

No complications were observed in patients receiving methenamine in the standard treatment for acute cystitis in adults at dose levels of 2 to 4 g/d (corresponding to about 28 to 57 mg/kg bw/d based on a body weight of 70 kg) for a 7- to 10-day course up to four weeks. Methenamine is also used for long-term suppressive therapy or for prevention of recurrent urinary infections (prophylaxis) because acquired resistance does not appear to develop. The usual oral dose of methenamine (methenamine hippurate or methenamine mandelate) for long-term treatment (6 months or longer) is 2-4 x 1 g/d (corresponding to ca. 28-57 mg/kg bw/d based on a body weight of 70 kg) No relevant side effects from the treatment with this dose level were reported.

A NOAEL of 4 g/d (57 mg/kg bw/d based on a body weight of 70 kg person) methenamine in man is derived from decades of long experience with methenamine as a therapeutic substance.