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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 1958
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Pamabrom, a bromotheophylline salt of AMP is an Over the counter (OTC) pharmaceutical product. This product has enhanced diuretic activity (Patent 2, 711, 411), and is used as a therapeutic agent in the relief of pre-menstrual tension (PMT). PMT is a common phenomenon observed in ~ 30-60% of women during their menstrual age.
Pamabrom (Bioequivalence study done on this product in 2018) has ~74% Bromotheophylline and ~ 26% AMP (1:1 molar ratio)

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
74% Bromotheophylline and ~ 26% AMP (1:1 molar ratio)

3. ANALOGUE APPROACH JUSTIFICATION
Bioequivalence of Pamabrom and AMP was evaluated using a single dose bioequivalence study. The extent of product bioavailability is estimated by the area under the blood concentration vs time curve (AUC). The bioequivalence results showed the 90% confidence interval was from 1.050 to 1.465
for Cmax, from 0.921 to 1.177 for AUC0-t, from 0.848 to 1.099 for AUC0-inf and from
0.929 to 1.177 for AUC0-168.
The results indicated that Pamabrom and AMP were equivalent for AUC0-t, AUC0-inf and AUC0-168


4. DATA MATRIX

Data source

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
repeated dose toxicity: oral
Principles of method if other than guideline:
- Principle of test:
- Short description of test conditions: Pamabrom was administered to pregnant women with edema-47 clinical trial
- Parameters analysed / observed: Special charts were kept on all patients, giving the age, parity, gravidity. gestation, usual weight, history of previous pregnancies, urine albumin (before
and after treatment on outpatients, daily on inpatients), urinary sodium,
chloride, potassium, creatinine (before treatment and on the fifth or seventh dav
of treatment of inpatients), blood pressure (before, during, and after treatment)
, daily intake and output of fluids (on inpatients), edema before and after
treatment, medication of nausea, vomiting, changes in vision, changes ill fatal
movement, headache, and miscellaneous side effects.
GLP compliance:
no

Test material

Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Pamabrom
- Expiration date of the lot/batch: n/a
- Purity test date: n/a

RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity:
- Specific activity:
- Locations of the label:
- Expiration date of radiochemical substance:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:
- Stability under test conditions:
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
- Preliminary purification step (if any):
- Final dilution of a dissolved solid, stock liquid or gel:
- Final preparation of a solid:

FORM AS APPLIED IN THE TEST (if different from that of starting material)

TYPE OF BIOCIDE/PESTICIDE FORMULATION (if applicable)

OTHER SPECIFICS:
- measurement of pH, osmolality, and precipitate in the culture medium to which the test chemical is added:
- other information:

Method

Type of population:
other:
Subjects:
Pregnant women with edema
Ethical approval:
not specified
Route of exposure:
oral
Reason of exposure:
intentional
Exposure assessment:
measured
Details on exposure:
Oral dosing of Pamabrom

Results and discussion

Clinical signs:
Diuresis of sodium, chloride and potassium ions and no side effects in the doses given
Results of examinations:
No side effects
Effectivity of medical treatment:
Effective in treating edema of pregnancy

Applicant's summary and conclusion

Conclusions:
800-1600 mg daily (25% AMP= 200-400 mg/person/day)= 2.86- 5.7 mkd ( for a 70 kg individual) on oral exposure caused no toxic effects in pregent women ( sensitive population)
Executive summary:

NOAEL for AMP from the repeated dose oral study in women is 2.86- 5.7 mkd ( for a 70 kg individual)