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Description of key information

It can be summarized that repeated dosing of high doses of valsartan (200 to 600 mg/kg/day) caused a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and changes in renal hemodynamics (slightly raised BUN, and renal tubular hyperplasia and basophilia in males) in rats. In marmosets at comparable doses, the changes were similar though more severe, particularly in the kidney where the changes developed to nephropathy including raised BUN and creatinine. Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by an exaggerated pharmacological action of valsartan which produced prolonged hypotension, particularly in marmosets.

Given the wealth of clinical data which have accumulated over the many years of use in man, data on repeated dose toxicity in animals are not considered of real relevance.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Feb 1992 - Sep 1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
no guideline followed
Principles of method if other than guideline:
To determin the toxicity of CGP 48933, an angiotensin II antagonist and therefore a potential antihypertensive, by oral gavge, in rats, during daily administartion for 6 months (interim treatment period) or 12 months (main treatment period) and, following the main treatment period, to asses the recovery from any toxicological effects after one month without treatment.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Tif:RAtf (SPF)
Sex:
male/female
Route of administration:
oral: gavage
Details on route of administration:
Administration: daily by oral gavge. The test substance was suspended in 0.5% carboxymethylcellulose and 0.5% Tween 80 at the requisite cocncentrations and given at constatnt volume of 10 ml/kg. Controls received the vehicle similarity.
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% Tween 80
Details on oral exposure:
Administration: daily by oral gavge. The test substance was suspended in 0.5% carboxymethylcellulose and 0.5% Tween 80 at the requisite cocncentrations and given at constatnt volume of 10 ml/kg. Controls received the vehicle similarity.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken during pre-test and on the day 15, 105, 156, 225, 295, 352 and 353.
Duration of treatment / exposure:
daily administartion for 6 months (interim treatment period) or 12 months (main treatment period) and, following the main treatment period, to asses the recovery from any toxicological effects after one month without treatment
Frequency of treatment:
daily administartion
Dose / conc.:
20 mg/kg bw (total dose)
Dose / conc.:
60 mg/kg bw (total dose)
Dose / conc.:
200 mg/kg bw (total dose)
No. of animals per sex per dose:
DOSE No of Rats
Control 35m + 35f
20mg/kg 35m + 35f
200mg/kg 35m + 35f

DURATION
10m and 10f killed at 6 months in each group
20m and 20f killed at 12 months in each group
5m and 5f for the recovery period in each group
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
Mortalities Daily
Clinical signs Daily
Body Weights Daily, reported weekly
Food consumption Weekly
Water consumption Daily, reported Weekly
Ophthalmic Examinations All rats during the pre-test period on 15m and 15f from control group and high dose (200mg/kg) animals during weeks 13, 26, and 52 and on all surviving animals from control group and high dose during week 4 of the recovery period
Hearing Examinations All rats during the pre-test period on 15m and 15f from control group and high dose (200mg/kg) animals during weeks 13, 26, and 52 and on all surviving animals from control group and high dose during week 4 of the recovery period
ECG Examinations On 3m and 3f from all groups and at pre-test pand weeks 12, 25, and 51 and during week 3 of the recovery period
Blood Chemistry All rats during the pre-test period and weeks 13, 26, and 52 and week 4 of recovery.
Haematology All rats during the pre-test period and weeks 13, 26, and 52 and week 4 of recovery.
Urinalysis All rats during weeks 11, 24, and 50 and week 4 of recovery.
Necropsy On all rats.
Organ Weights On all rats killed at the end of the interim treatement period, main treatment period and recovery period.
Microscopy Where possible, a full examination was made on all tissues from all control and high dose rats killed during and at t he end of the interim and main treatment periods.
Sacrifice and pathology:
On all rats.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No clinical signs were observed that were considered to be due to trealrnent
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No deaths occurred that were considered to be due to treatment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Males receiving 200 mg/kg or 60 mg/kg showed a slight dose related decrese In body weight gain from week 8 to week 26 of lhe study. During
weeks 27 to 52, body weight gains were reduced only in males receiving 200 mg/kg CGP 48 933. Males receiving 20 mg/kg and females showed no treatment related effects. An apparent difference in group mean body weight from controls during the latter half of the treatment period in males treated at 20 mg/kg was atlrlbuted to changes In group means following the Interim kill, and not to treatment.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
There was a transient reduction In food consumption In males receiving 60 mg/kg and 200 mg/kg seen as very slight by lower total amounts of food consumed during the treatment period. Over the whole trealment period, this difference fom controls was approldmately 5%. During the first 26 weeks of treatment the difference from controls was sllghdy greater but did not exceed 10% in high dosage males except at week 13. During that week males receiving 200 mg/kg ate approximately 14% less than control males; this Isolated occurrence was not considered to be of toxlcologlcal significance.
Females showed no treatment related effects.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Males receiving 200 mg/kg showed increased water consumption throughout the treatment period when compared with control animals. The difference from controls, which varied between approximately 15% and 30%, remained similar throughout the treatment period. During the frst five weeks of treatment there was some evidence of a minor increase In water consumption in males treated at 60 or 20 mg/kg.
Females showed no treatment related effects.
Ophthalmological findings:
effects observed, non-treatment-related
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
200mg/kg - Both sexes showed a sight drop in measured red cell parameter values only. This effect was more apparent in male rats where individual animals with low haemoglobin concentration tended to have raised reticulocyte levels.

60 and 20mg/kg There were no treatment related abnormalities.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg
Plasma urea concentrations were moderately raised in males throught the treatment period and slightly raised in females only at weeks 13 and 26. Cholesterol concentrations in males were slightly decreased at week 26 and moderate decreased at week 52. Triglyceride levels in male animals were slightly decreased at week 13 and 26, and moderately decreased by week 52. The total protein concentration in males only was slightly decreased at week 52. Plasma potassium concentrations were slightly raised in males and females at week 13 and in males only at weeks 26 and 52. There were similar minor increases in plasma magnesium in males only.
20mg/kg
The cholesterol level of male animals was slightly decreased at week 52.

All changes in blood biochemistry are considered to be related to the pharmacological activity of the test article, and were absent at week 4 of recovery.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
There were a slight decrease in the mean sodium output of male animals at 200mg/kg during the treatment period.
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Slightly lower heart weights after 26 and 52 weeks in males at 200mg/kg were tought to be related to the pharmacologic action of this antihypertensive compound and is normally observed in studies with ACE inhibitors. Renal arteriolar hypertrophy at 200 mg/kg/day
The findings was absent in animals of the recovery group.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
Treatment related effects occurred at all doses, and included: 1) decreased body weight gain and food consumption at 60 mg/kg/day or higher; 2) increased water consumption and urine volume at all doses; 3) decreased urinary sodium at 200 mg/kg/day; 4) increased BUN and potassium starting at 60 mg/kg/day, and increased magnesium at 200 mg/kg/day; 5) decreased cholesterol at all doses, triglyceride at 60 mg/kg/day or higher, and total protein at 200 mg/kg/day; 6) anemia at 200 mg/kg/day; 7) decreased heart weights at 200 mg/kg/day; and 8) renal arteriolar hypertrophy at 200 mg/kg/day.


All changes were considered to be secondary to the pharmacological activity of the test material, an angiotensin II antagonist, and were not evident after 4 weeks of recovery; therefore it was considered that the 200mg/kg dosage represents the no adverse effect level in this study.
Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
haematology
mortality
ophthalmological examination
organ weights and organ / body weight ratios
urinalysis
water consumption and compound intake
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
200 mg/kg diet
System:
urinary
Organ:
blood
heart
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
All changes were considered to be secondary to the pharmacological activity of the test material, an angiotensin II antagonist, and were not evident after 4 weeks of recovery; therefore it was considered that the 200mg/kg dosage represents the no adverse effect level in this study.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
chronic
Experimental exposure time per week (hours/week):
7
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

In controlled clinical studies in adult patients with hypertension, the overall incidence of adverse reactions (ADRs) was comparable with placebo and is consistent with the pharmacology of valsartan. The incidence of ADRs did not appear to be related to dose or treatment duration and also showed no association with gender, age or race.

The following events have been observed during clinical trials in hypertensive patients irrespective of their causal association with the study drug: arthralgia, asthenia, back pain,

diarrhea, dizziness, headache, insomnia, libido decrease, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.

Hypertensive patients with Impaired Glucose Tolerance at cardiovascular risk

In the NAVIGATOR study, adverse events with DIOVAN were similar to those reported previously for patients with hypertension.

Post-myocardial infarction and/or heart failure

The safety profile seen in controlled-clinical studies in patients with post-myocardial infarction and/or heart failure varies from the overall safety profile seen in hypertensive patients. This may relate to the patients underlying disease. ADRs that occurred in post-myocardial infarction and/or heart failure patients are as follows:

Dizziness, postural dizziness (common); hypotension, orthostatic hypertension (common); renal failure and impairment (common)

Additional information

Post-Marketing Experience

In addition to the safety experience gained from clinical trials, analysis of adverse event reports received from the market since the first introduction in 1996 has revealed very rare cases of angioedema, rash, pruritus, and other hypersensitivity/allergic reactions including serum sickness and vasculitis. Very rare cases of impaired renal function have also been reported. In addition, myalgia was observed as a rare adverse event with valsartan in a Prescription-Event-Monitoring study of around 13,000 patients in England [CRD-49]. Another study of monitoring adverse events in England reported that dyspnea was one of the most commonly reported events in association with valsartan. Based on post-marketing reports, several European countries have included the occurrence of very rare cases of bleeding and thrombocytopenia in association with valsartan into the local product information. Based on post-marketing reports, hyponatremia was added to the local product information in the EU.

Exposure in number of patient treatment years was calculated on the basis of sales data assuming an average daily dose of one tablet per day per patient. Total exposure to valsartan until 30 Apr 2014 is approximately 95 million patient treatment years for adults and 28,654 patient treatment years for pediatric use based on the amount of valsartan tablets sold.

(Ref.: Investigators Brochure, Edition 24, December, 2014)

Justification for classification or non-classification

It can be summarized that repeated dosing of high doses of valsartan (200 to 600 mg/kg/day) caused a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and changes in renal hemodynamics (slightly raised BUN, and renal tubular hyperplasia and basophilia in males) in rats. In marmosets at comparable doses, the changes were similar though more severe, particularly in the kidney where the changes developed to nephropathy including raised BUN and creatinine. Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by an exaggerated pharmacological action of valsartan which produced prolonged hypotension, particularly in marmosets.

Given the wealth of clinical data which have accumulated over the many years of use in man, data on repeated dose toxicity in animals are not considered of real relevance.

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