[Evaluated Articles] Product name: Lipitor, Lipitor 5mg Tablet, Lipitor 10mg Tablet
Generic name: atorvastatin calcium hydrate
24th August 1998 (Import approval of the drug substance,
manufacturing approval of the drug product)
Drug product: Yamanouchi Pharmaceutical Co., Ltd
Evaluation Division II, Pharmaceuticals and Medical Device
Evaluation Centre, National Institute of Health Sciences
As a result of evaluation by the Pharmaceuticals and Medical Device Evaluation Centre
and discussion by the 2nd Subcommittee on New Drugs, we have no objection in granting
Usually for adults, orally administer 10mg of atorvastatin once daily
Usually for adult, orally administer 10mg of atorvastatin once daily
The dose should be adjusted according to age and symptoms. In severe cases,
the dose may be increased to up to 40mg per day.
EVALUATION SUMMARY (PART 1)
Pharmaceuticals and Medical Device Evaluation Centre
1. SUMMARY OF THE ARTICLES
Lipitor, Lipitor tablet 5mg, Lipitor tablet 10mg
24th August 1998 (Import approval of the drug substance,
manufacturing approval of the drug product)
Drug product: Yamanouchi Pharmaceutical Co., Ltd
Film coat tablets containing 5mg or 10mg of atorvastatin per
Usually for adults, orally administer 10mg of atorvastatin once daily
Usually for adults, orally administer 10mg of atorvastatin once daily
The dose should be adjusted according to age and symptoms. In severe
cases, the dose may be increased to up to 40mg per day.
2. SUMMARY OF THE SUBMITTED DATA AND EVALUATION BY THE
A. Data On Origin, Details of Discovery, Use in Overseas Countries, etc.
Atorvastatin is a HMG-CoA reductase inhibitor for treatment of hyperlipidemia, which
was synthesised by Warner-Lambert (US) in 1986. It is approved in 68 countries
including the UK, Germany and the USA (as of March 1999).
In addition to non-clinical and clinical studies implemented by Warner-Lambert (US),
non-clinical studies were implemented in Japan. The Japanese clinical study program
was started in November 1992. In November 1993, Warner-Lambert and Yamanouchi
Pharmaceuticals concluded a joint development contract. Since then, the two companies
implemented joint non-clinical and clinical studies and came to apply for an importing
approval of the drug substance for Warner-Lambert and a manufacturing approval of the
drug products for Yamanouchi Pharmaceutical.
In December 1994, the production method of the drug substance was improved and the
amorphous drug substance was replaced with a more stable and purer crystalline drug
substance. In Japan, the Applicant used formulations with the crystalline drug substance
from phase IIb clinical studies onward.
B. Data on Physical and Chemical Properties, Specifications and Test Methods,
With regard to specifications and test methods of the drug substance, the Evaluation
Centre instructed the Applicant to specify optical rotation as a specific physical and
chemical value for the Identification Test and to review the specification of heavy metal
in the Purity Test. In addition, they asked for more detailed discussion on the safety of
related substances. Referring to a replacement of the amorphous drug substance with
the crystalline drug substance, the Evaluation Centre instructed the Applicant to provide
information on their differences in stability and dissolution speed. Furthermore, they
instructed the Applicant to amend the Gaiyo
according to data from analysis validations.
The Applicant supplied appropriate responses to those instructions and the Evaluation
Centre verified that appropriate specifications and test methods were set up.
C. Data on Stability
With the drug substance, slight degradation due to temperature, and slight degradation
and colouring due to light were observed. No change due to storage was observed in the
long-term storage study (24 months) and the accelerated study. The drug substance was
considered to be stable for a minimum of two years at ambient temperature.
Changes in the drug products were observed under open temperature/humidity
conditions. However, when the drug products were packed in sealed plastic bottles with
desiccators or PTP/metal strips, few changes were observed in the long-term storage
study and accelerated study. Change due to light was negligible at 1,440,000 lux/hour.
In conclusion, the formulated products were considered to be stable for a minimum of
The long-term study of the drug substance and the drug products is still on-going.
D. Data on Acute Toxicity, Subacute Toxicity, Chronic Toxicity, Teratogenicity
and Other Toxicity
Acute toxicity studies were implemented in rats and dogs.
LD50 of a single oral dose in rats was 5000mg/kg or over and approximate lethal dose of
a two-week dose escalation in dogs was 400mg/kg or over.
Subacute toxicity and chronic toxicity studies were implemented in rats and dogs with
oral dose. Main toxicological findings were increases in serum transaminase and skeletal
muscle degeneration/necrosis. Increases in the liver weight and cornification of mucosa
of forestomach in rats and suppression of body weight gain and cholestasis in the liver in
dogs were observed, but they were reversible after withdrawal except for the liver
histology. In the subacute toxicity study, the no toxicity doses were 5mg/kg/day in male
rats, 20mg/kg/day in female rats and 10mg/kg in dogs. In the chronic toxicity study, the
no toxicity doses were 5mg/kg/day in rats and 10mg/kg/day in dogs.
The Evaluation Centre instructed the Applicant to provide a clarification on safety
because the no toxicity dose in rats was relatively low. The Applicant argued that an
intrinsic no toxicity dose was 70mg/kg/day, which was approximately 88 times higher as
a dose amount than the human clinical dose (0.2 to 0.8 mg/kg). The Evaluation Centre
instructed the Applicant to provide an account for the liver effect. The Applicant replied
that hepatic impairments in rats and dogs were not qualitatively serious and dosage
within a normal range was unlikely to cause serious hepatic impairment in humans. We
would like to hear the Subcommittee’s comments on this response.
Reproductive and developmental toxicity studies were implemented in rats and rabbits.
In the male fertility study in rats and the female fertility study in rats, suppressions of
body weight gain and reductions of food consumptions were observed in parent animals,
however, effect on reproductive potentials and early embryonic development was not
observed. The no toxicity dose in male parent animals was estimated at 20mg/kg/day
and that for female parent animals was at 100mg/kg/day.
In the organogenesis study in rats, dams showed suppression of bodyweight gain,
reduction in food consumption and hypersalivation. At 300mg/kg/day, reduction in
foetal bodyweight and embryonic lethality were observed, but teratogenicity was absent.
The estimated no toxicity dose was 100mg/kg/day in both dams and foetuses.
The rabbit organogenesis study showed suppression of bodyweight gain in dams and an
increase in the mortality of dams after nidation, but teratogenicity was absent. The no
toxicity dose was estimated at 10mg/kg/day in dams and 50mg/kg/day in foetuses.
In the organogenesis, peri- and postnatal study in rats, suppression of bodyweight gain
and reduction in food consumption were observed in dams. Bodyweight reduction in
offspring, developmental delay in offspring and reduced responses in some behavioural
function tests were observed in the second generation. The no toxicity dose was
estimated at 100mg/kg/day in dams and 20mg/kg/day in the second generation.
Results of antigenicity tests were negative.
In the mutanogenicity study, microbial reverse mutation tests, chromosome aberration
tests with mammalian cell cultures and mouse micronucleus tests were performed, and all
Carcinogenicity studies were carried out in mice and rats. An increase in the incidence of
hepatocellular tumours in mice was observed at 400mg/kg/day.
The Evaluation Centre instructed the Applicant to discuss carcinogenic potential in
humans. The Applicant believed that the increase in hepatocellular tumours was due to
the liver effect which was specific to rodents and possibility of increase in hepatocellular
tumours in humans was low. The Evaluation Centre accepted the response.
Neither a dependency study nor a local irritation study were carried out.
The amorphous drug substance was used in the above toxicity studies. In order to
confirm that the crystalline drug substance was not toxicologically different from the
amorphous drug substance, which was replaced with the crystalline drug substance
during the development, bridging toxicity studies were implemented in mice, rats and
In mice and rats, there was no difference in the toxicology of these drug substances.
However, in dogs, the crystalline drug substance had a tendency to show higher plasma
concentrations and stronger toxicity.
Compared with the toxicity of other agents, the toxicity seen in atorvastatin was
common to other HMG-CoA reductase inhibitors and specific toxicity was not observed.
E. Data on Pharmacological Action
studies (human hepatocellular carcinoma HepG2 cells, rat liver microsome
fraction and rat liver, spleen and testis tissue preparations) demonstrated that atorvastatin
had HMG-CoA reductase inhibitory effect and inhibitory effect on cholesterol synthesis
and it increased LDL receptor activities and LDL receptor mRNA expression. Strengths
of tissue selectivity of cholesterol synthesis inhibitions of various agents in the liver tissue
preparations were compared on a base of their relative IC50. The agent with the
strongest selectivity was pravastatin (2 to 3) followed by atorvastatin (1), and the lowest
When normal guinea pigs, which were believed to have cholesterol metabolisms similar
to humans, received repeated oral doses of atorvastatin for two weeks, an increase in the
LDL receptor activity in the liver microsome fraction, a decrease in the total cholesterol
(TC) levels in the liver and reduced plasma TC levels were observed. When sucrose-fed
hypertriglyceridaemia rats received repeated oral doses of atorvastatin for two weeks,
reductions in serum triglyceride (TG) levels and TG secretion speed were observed.
Repeated oral dose studies in Watanabe
heritable hyperlipidemic rabbits and cholesterol-
fed rabbits showed serum TC lowering, reduction in percentages of diseased area and
cholesterol contents in the thoracic aorta, and reduced area with intimal thickening in the
iliofemoral aorta. Repeated oral doses of atorvastatin in cholestyramine-fed dogs
lowered plasma TC levels. In cholesterol-fed miniature pigs, the speed of LDL and
VLDL apoprotein B synthesis in the liver was reduced. When atorvastatin was
repeatedly administered orally for three weeks, plasma TC levels, LDL-cholesterol
(LDL-C) levels, TG levels and VLDL-TG levels were reduced.
In a study with rat liver microsome fractions, the main metabolites in humans, which
were hydrated at the 4th position (M-1) and 2nd position (M-2) of the amide band of the
benzene ring, demonstrated HMG-CoA reductase inhibitory effect. The degree of the
inhibitory effect was similar to the parent form.
In conclusion, it was suggested that atorvastatin inhibited cholesterol synthesis in the
liver and induced hypermetabolism of blood lipoprotein by LDL-receptors. At the same
time, it prevented arteriosclerosis associated with hyperlipidemia by improving blood
kinetics of lipids through reducing the speed of secretion and synthesis of lipoproteins.
As a part of the general pharmacological actions, atorvastatin reduced motor activities in
rats. The metabolite (M-2) transiently reduced the urine volumes and K+ excretion levels
The Evaluation Centre compared the PK/PD in order to assess appropriateness of the
clinical dose against the effective dose in animals. IC50 of inhibitory effect on cholesterol
synthesis in rat liver tissue preparations was 39mM (45ng/mL). IC50 of inhibitory effect
on cholesterol synthesis in the liver microsome of cholestyramine-fed rats were 13nM
(15ng/mL). When a single dose of atorvastatin (3mg/kg) was given to cholestyramine-
fed rats, the rate of the cholesterol synthesis inhibition was 43% and the cholesterol
synthesis was significantly inhibited for up to four hours after dosing. Rat plasma free
parent-form concentrations at four hours after dosing were approximately 0.2 to
0.5ng/mL (plasma protein binding rate: 94.9 to 97.7%) and the tissue-plasma
concentration ratio in the liver was around 130. Therefore, the free parent-form
concentration in the liver was estimated at around 27 to 60ng/mL. This was roughly in
agreement with IC50 of the inhibitory effect on cholesterol synthesis in the rat liver tissue
preparations. The free M-2 concentration in the liver (plasma protein binding rate in
humans: 96.6 to 98.9%) was estimated at around 30 to 93ng/mL.
IC50 of inhibitory effect on cholesterol synthesis in HepG2 cells was 70nM (81ng/mL).
The Applicant set the dose for hyperlipidemia patients at 10mg/dose/day
(0.17mg/kg/day), which may be increased to 20mg/dose/day. In a seven-day repeated
dose study in the clinical phase I program, serum lipid tests were performed before
breakfast and 10mg of atorvastatin was administered after breakfast. Compared to
predose levels, postdose serum lipid levels were significantly reduced (22% reduction in
the TC value). When healthy volunteers received repeated doses of the crystalline
formulation, estimated concentrations of plasma free parent-form before breakfast on
Day 7 were approximately 0.01 to 0.06ng/mL (plasma protein binding rate: 95.6 to
99.0%). Presuming transposition of atorvastatin to organs was similar in rats and
humans, the free parent-form concentration in the liver before breakfast was estimated at
approximately 3 to 13ng/mL and the free M-2 concentration in the liver was estimated at
approximately 2 to 5ng/mL (plasma protein binding rate: 96.6 to 98.9%). Even if their
effects were additive, they were closer than IC50 of inhibitory effect on cholesterol
synthesis in HepG2 cells. However, after administration, the IC50 values were closer.
In a Japanese study in homozygotic familial hypercholesterolemia patients, atorvastatin
with or without concurrent probcol was effective in lowering TC and LDL-C in two
patients with a partial deficit of LDL receptors (48.37%) with high receptor activities,
but the number of patients was insufficient for making efficacy assessment. Therefore,
the Evaluation Centre requested a justification of the indication to homozygotic patients.
The Applicant replied that because plasma TC levels and the speed of cholesterol
excretion were reduced in LDL receptor deficient mice (a model for familial
hypercholesterolemia), atorvastatin’s effect was not restricted to LDL receptors and
homozygotic patients were rare (one in one million), they added a precaution for
homozygotic patient treatment in the Precautions for Use. Furthermore, the Evaluation
Centre instructed the Applicant to provide details of currently available information on
the mode of the TG lowering effect. The Applicant replied that the amount of TG in the
liver did not show changes despite the inhibitory effect on TG excretion and details about
F. Data on Absorption, Distribution, Metabolism and Excretion
When healthy volunteers received a single oral dose of 5 to 40mg atorvastatin, plasma
parent-form concentrations reached the maximum (Cmax) at 0.6 to 0.9 hours from the
administration and the biological half-life (t1/2) was 9.4 to 10.7 hours. The Cmax and the
area under the plasma concentration-time curve (AUC0-∞) increased roughly
proportionally to the dosed amount. The bioavailability of atorvastatin (as the parent
form) was 12.2%. Compared with administration under fasting conditions, time to the
maximum plasma concentration (Tmax) of administration after meals was prolonged and
the Cmax was reduced to less than a half, but t1/2 and AUC0-∞ were almost unchanged.
Cmax and AUC of the plasma parent-form after repeated oral doses of 10mg/day were 1.2
times to 0.9 times of those after a single dose and a steady state was achieved within four
days of administration. Tmax and t1/2 of the plasma active metabolite M-2 concentrations
after an oral dose of 10mg atorvastatin in healthy volunteers were 6.2 hours and 8.0
hours, respectively. The AUC0-48hr was about a half of that of the parent form,
suggesting contribution of M-2 to the manifestation of a therapeutic response. The
plasma M-1 concentration was extremely low.
In elderly population, Cmax and AUC0-∞ of the plasma parent-form were about twofold
higher than in younger population. Their plasma M-2 concentrations were also about
twofold higher than in the younger population, demonstrating effects of aging. In
hyperlipidemia patients (foreign population), Cmax and AUC of plasma HMG-CoA
reductase inhibition active substances (the active forms) were about two times higher
than in healthy volunteers (Japanese). Plasma active-form concentrations in subjects
with cirrhosis were significantly higher than subjects with normal liver function (both in
When 40mg of 14C-atorvastatin was orally administered to subjects (foreign) after
cholecystectomy, the excretion rates of the parent form, M-1 and M-2 in the bile were
5.3%, 5.7% and 2.7% of the dosed amount respectively, and the total excretion rate in
the bile was 57.0%. When 20mg of 14C-atorvastatin was orally administered to healthy
volunteers (foreign), 8.3%, 11.7% and 18.2% of radioactivity in the faeces were the
parent form, M-1 and M-2, respectively. The total volume of excretion was 1.2% in
urine and 89.4% in faeces. In human, atorvastatin was mainly metabolised in the liver
and involvement of CYP3A4 as the main metabolising enzyme was suggested.
Drug interactions were investigated abroad. Concurrent use of aluminium hydroxide gel/
magnesium hydroxide preparations or negative ionic exchange resins inhibited
atorvastatin absorption. Concomitant use of erythromycin increased plasma active-
atorvastatin concentrations. It also increased plasma norethindrone/ethinylestradiol
concentrations, digoxin concentrations and terfenadine concentrations.
During the clinical program, the drug substance was changed from amorphous to
crystalline. With regard to studies in hyperlipidemia patients, the amorphous formulation
was only used in the phase IIa studies. Comparison of pharmacokinetic parameters of a
single dose in healthy volunteers showed AUC0-∞ of the crystalline formulation was 32%
higher than the amorphous formulation. Formulations with different contents were also
compared. Two 5mg tablets and one 10mg tablet of atorvastatin (the crystalline
formulations) were biologically equivalent.
The absorption rate of 14C-atorvastatin in the in situ
rat digestive tract was the highest
in the duodenum, followed by the jejunum then the stomach, and the lowest in the ileum.
When male rats received 3mg/kg of atorvastatin orally, Cmax was 40ng/mL and t1/2 was
1.5 hours. Within a dose range of 1 to 10mg/kg, Cmax and AUC0-∞ of the plasma parent-
form increased roughly proportionally to the dosed amount. Cmax was lower in females
than in males and showed durable changes in females. When dogs received oral doses,
an increase in plasma parent-form concentrations was bigger than an increase in the
dosed amounts, but there was no sex difference. Bioavailability of an oral dose was
between 9 and 14% in rats, and between 13 and 25% in dogs.
When rats received a single oral dose of 14C-atorvastatin, radioactivity was accumulated
specifically in the liver and it was 130 times of the highest plasma concentration at four
hours after administration. Between 34 and 53% of radioactivity was located in blood
cells, and the in vitro
plasma protein bonding rate of 14C-atorvastatin in mice, rats, dogs
and human was between 95 and 99% in all species. Main bonding proteins were LDL,
HDL and albumin. In humans, the in vitro
plasma protein bonding rate of the active
metabolite M-2 was similar to that of the parent form and a protein binding interaction
between the parent form and M-2 was not observed. It was considered that atorvastatin
did not have a protein binding interaction with any of concurrent drugs examined.
Rat, dog and human in vitro
liver microsome metabolisms produced M-1 and M-2,
showing no difference among species. The main metabolite in plasma after an oral dose
in rats and dogs was M-2 in both species and the AUC0-∞ was bigger than that of the
In rats and dogs, the rate of radioactivity excretion in urine after oral administration of
14C-atorvastatin was 2.0% and 3.0% respectively, and the rate of excretion in faeces
was 98.5% and 96.2% respectively. The rate of excretion in bile was 66.9% in rats,
suggesting a presence of enterohepatic circulations. In rats, there was no sex difference
in excretion rates via urine, bile and faeces.
At four hours after pregnant rats received an oral dose, radioactivity in the foetuses was
5% of plasma concentrations in dams, showing a slight transmigration. When lactating
rats received 14C-atorvastatin orally, radioactivity was eliminated faster from milk than
from plasma. In the liver of weaning pups, a low level of radioactivity was found,
suggesting absorption of compounds in milk in the digestive tract.
As the plasma concentrations in cirrhosis patients were significantly higher, the
Evaluation Centre requested the Applicant to compare it with other HMG-CoA
reductase inhibitors. It was suggested that atorvastatin, lovastatin, simvastatin,
pravastatin and fluvastatin were likely to be affected by changes in liver function, because
all of them were mainly metabolised in the liver and excreted to the bile. Pravastatin and
fluvastatin were also reported to have significantly higher Cmax and AUC in cirrhosis
patients than in the healthy population. The Applicant argued that Cmax and AUC in
cirrhosis patients were significantly higher because a proportion of orally administered
atorvastatin entered the systemic circulation directly from the portal system avoiding the
first pass effect. However, the 9.8-fold increase of AUC in moderate cirrhosis patients
was not fully accounted for by this because the absolute bioavailability of atorvastatin
was 12.2% and even if 100% of atorvastatin was absorbed and entered the systemic
circulation directly, the AUC increase would be only around 8-fold. In addition, based
on the distribution after repeated doses in rats, assuming only the parent form was
accumulated in the liver, an estimated free parent form concentration in moderate
cirrhosis patients was approximately 850ng/mL. The Michaelis constant of atorvastatin
metabolism based on free atorvastatin was estimated at 52 to 58 mM, therefore, the
increases were not caused by saturated metabolisms.
The Evaluation Centre asked the Applicant to provide details of drug interactions of
atorvastatin including comparisons with other HMG-CoA reductase inhibitors. It was
considered that plasma active atorvastatin concentrations were increased with
concomitant use of erythromycin because erythromycin formed p-450-macrolide
metabolite complex, which deactivated P450 enzymes. This was also observed in other
HMG-CoA reductase inhibitors. The Applicant stated that atorvastatin, simvastatin and
cerivastatin were mainly metabolised by CYP3A4 and therefore care should be taken
when a CYP3A4 matrix such as terfenadine was used concomitantly. Concomitant use
of itraconazol increased AUC of unchanged atorvastatin threefold. The Evaluation
Centre believed that in some cases, a dose adjustment might be required when a strong
inhibitor of CYP3A4 was used concurrently.
The mode of action of the increase in blood digoxin concentration with a concurrent use
of atorvastatin and digoxin had not been explained. The Evaluation Centre requested an
interpretation of a possibility of active excretion to the digestive tract cavity. The
Applicant responded that an investigation using the human colon cancer Caco-2 cell
culture suggested a membrane transport via the monocarboxylate transport system
(proton co-transporters) on the brush border membrane of epithelocyte of small intestine
and secretion to the digestive tract cavity via the p-glycoprotein transport system.
The incidence of abnormal changes in lab test values with atorvastatin was 38%, which
was higher than those observed with existing HMG-CoA reductase inhibitors (7 to
19%). The 21-day repeated oral dose distribution study in rats showed that
accumulation of radioactivity in the liver at four hours after administration on Day 21
was 1.7 times higher than after a single dose, raising concerns over hepatopathy. The
plasma protein-binding rate was extremely high but the Evaluation Centre believed that
there would be no clinically significant effect because the distribution volume at the
G. Data on Clinical Study Results
The clinical program was carried out from November 1992 till May 1998 targeting 1112
Combining a phase I single dose study and a phase I single/repeated dose study, safety
assessment of 2.5mg to 40 mg atorvastatin was carried out in 30 subjects. Four out of
five subjects in the 40mg group had adverse events including heavy head and stomach
pain, one out of six subjects in the 20mg group showed elevated bilirubin and one out of
six subjects in the 10mg group showed elevated GOT and GPT.
A phase IIa study targeted 121 hyperlipidemia patients with TC levels of 220mg/dL or
over and TG levels of not more than 400mg/dL which were measured more than twice in
the predose-observation period. The study was in the double-blind parallel-groups
design with four groups at the dose levels of placebo, 5mg, 10mg and 20mg, receiving
the study treatment for eight weeks. The percentage change of TC and LDL-C levels
were -0.7±10.7% and -1.5±11.6% in the placebo group, respectively, whereas they were
-28.0±8.6% and -27.4±12.2%; -37.9±8.5% and -36.5±12.5%; and -38.4±15.7% and -
49.6±9.7% in the 5mg, 10mg and 20mg groups, respectively. The percentage change of
TG levels was 20.9±42.3% in the placebo group, whereas they were -19.0±28.5%, -
17.2±31.3% and -24.2±27.2% in the 5mg, 10mg and 20mg groups, respectively. The
incidences of adverse events other than abnormal changes in lab test values were 3.3%
(1/30 cases), 3.8% (1/26 cases), 12.5% (4/32 cases) and 9.7% (3/31 cases) in the
placebo, 5mg, 10mg and 20mg groups, respectively. Abnormal changes in lab test
results were seen in 26.7% (8/30), 26.9% (7/26), 40.6% (13/32) and 25.8% (8/31) of
patients in the placebo, 5mg, 10mg and 20mg groups, respectively.
A phase IIb study targeted 243 hyperlipidemia patients with TC levels of 220mg/dL or
over in all measurements which were taken more than twice in the observation period.
The study design was in a double-blind fashion with parallel-groups receiving 2.5mg,
5mg 10mg or 20mg of atorvastatin once daily after evening meals for 12 weeks. TG
levels were not used as inclusion criteria. Two hundred six patients were included in the
efficacy analysis. The percentage change of TC and LDL-C was -20.0±8.5% and -
25.0±8.8%; -30.2±9.0% and -33.8±8.6%; –29.1±9.6% and -32.0±11.3%; and -
39.6±16.0% and -49.5±11.4% in the 2.5mg, 5mg, 10mg and 20mg groups, respectively.
The percentage change of TG was –6.2±31.6%, -19.7±33.7%, -16.7±43.3% and -
12.0±48.8% in the 2.5mg, 5mg, 10mg and 20mg groups, respectively. However, the
numerical changes were 156.4±107.8→141.1±112.9mg/dL, 204.4±112.5→150.3
±83.4mg/dL, 184.6±141.9→131.9±85.5mg/dL and 134.7±85.2→100.0±45.5mg/dL,
respectively. The incidence of adverse events excluding abnormal changes in lab test
values in patients included in safety analysis was 5.0% (3/60), 12.1% (7/58), 7.0% (4/57)
and 10.3% (6/58), in the 2.5mg, 5mg, 10mg and 20mg groups, respectively. Abnormal
changes in lab test values were seen in 36.7% (22/60) of patients in the 2.5mg group,
34.5% (20/58) of the 5mg group, 33.3% (19/57) of the 10mg group and 46.6% (27/58)
A phase III study targeted 263 hyperlipidemia patients with TC levels of 220mg/dL or
over and LDL-C levels of 140mg/dL or over in all measurements which were taken more
than twice in the predose observation period. It was a 12-week double blind
comparative study of 10mg atorvastatin with a control drug of 10mg pravastatin. Two
hundred twelve patients were included in the efficacy analysis. In the atorvastatin group,
TC levels were 278.6±41.6mg/dL predose and 196.0±36.2mg/dL postdose, showing a
change of -29.4±9.6%, whereas in the control group, they were 285.4±44.8mg/dL
predose and 243.2±45.3mg/dL postdose, showing a change of -14.5±10.0%. The
atorvastatin group showed a significant decrease in TC levels. Similarly with LDL-C,
LDL-C levels in the atorvastatin group were 190.7±41.6mg/dL predose and
110.4±33.5mg/dL postdose, showing a change of -41.9±12.5%, whereas in the control
group, they were 195.5±44.3mg/dL predose and 152.8±43.9mg/dL postdose, showing a
change of -21.5±13.7%. The atorvastatin group showed a significant decrease in LDL-C
levels. With regard to TG, TG levels in the atorvastatin group were 166.1±78.3mg/dL
predose and 118.8 ±53.6mg/dL post dose, showing a change of -21.0±34.2%, whereas
in the control drug group, they were 177.5±90.4mg/dL predose and 151.8±75.0mg/dL
postdose, showing a change of -5.4±42.0%. The atorvastatin group showed a significant
decrease in TG levels. Increases in HDL-C levels were seen in both groups, which were
7.5±8.7mg/dL and 5.9±7.9mg/dL higher than the predose levels respectively, but there
was no difference between the groups. The incidence of adverse events excluding
abnormal changes in lab test values in the each group of patients included in the safety
analysis was 5.2% (6/116) in the atorvastatin groups and 9.1% (11/121) in the control
group. Abnormal changes in lab test values which may be relevant to the study drugs
were 37.1% (43/116) in the atorvastatin groups and 27.3% (33/121) in the control
group. The common events with atorvastatin were increased liver enzyme levels
including GOT, GPT and γ-GTP, elevated CPK, elevated glucose, elevated TSH and
reduced testosterone. One patient in the atorvastatin group who had elevated liver
enzyme levels was unable to continue with the study treatment and withdrawn from the
study. The rate of patients who scored “no issues” in the overall safety assessment was
79.3% (92/116) in the atorvastatin groups and 80.2% (97/121) in the control group,
Other clinical trials implemented included a 12-week phase IIa study in 29 hyperlipidemia
patients, a 52-week long-term study in 311 patients and a geriatric study in 57 elderly
subjects. In the 12-week study, two patients were withdrawn due to raised liver enzyme
levels. In the long-term study, two patients were withdrawn due to raised liver enzyme
levels and one patient was withdrawn due to raised biliary enzyme levels, etc.
In an open study in 24 heterozygotic familial hypercholesterolemia patients, a dose
amount of atorvastatin was increased every eight weeks starting from 10mg up to 40mg.
In line with the increasing dose, a trend of TC reductions was observed, but safety was
reduced as the dose increased. In the safety assessment, one patient in the 10mg group
with an adverse drug reaction of “weakness/lassitude of the back and lower extremities”,
one patient in the 10mg group with raised liver enzyme levels, two patients in the 20mg
group with raised liver enzyme levels and three patients in the 40mg group with raised
liver enzyme levels were regarded to have had “concerns” over safety.
In a dose escalation open study in nine homozygotic familial hypercholesterolemia
patients, a dose amount of atorvastatin was escalated from 10mg to up to 40mg. Three
homozygotic patients showed a reduction in TC and LDL-C levels of over 10%
compared with predose levels. However, other six cases showed deterioration; in
particular some negative type patients whose LDL receptor activities were minimumal,
Three clinical pharmacological studies were implemented investigating 1) effect on bile
lipids, 2) effect on the blood coagulation and fibrinolytic system and 3) effect on the
glucose metabolisms (placebo controlled). In the study investigating the glucose
metabolisms, one sudden cardiac death was reported but the subject was in the placebo
group. No other serious adverse drug reactions were reported.
In overseas clinical studies, which were mainly carried out in the West, 4,271 subjects
received atorvastatin (some were at more than one dose levels). The incidences of over
threefold increases from the normal upper limit of transaminase in more than two
successive tests were 0.2% (3/1843), 0.2% (2/892), 0.6% (5/811) and 2.3% (20/888) at
a dose level of 10mg, 20mg, 40mg and 80mg, respectively. Although data on
transaminase elevations with other HMG-CoA reductase inhibitors published in the
Physician’s Desk Reference were not necessarily suitable for a direct comparison because
1) approved doses were different and 2) incidences listed were not necessarily
frequencies of over threefold increases from the normal upper limit of transaminase in
“more than two successive tests”, the data showed that the incidences were 1.3% for
pravastatin (approved dose in Japan: 10 to 20mg, approved dose in the US: 10 to 40mg),
1.0% for simvastatin (Japan: 5 to 10mg, US: 5 to 40mg), 1.1% fluvastatin (Japan: 20 to
60mg, US: 20 to 80mg) and less than 1.0% for cerivastatin (Japan: 0.15 to 0.3mg, US:
0.3mg). The Applicant argued, therefore, that the incidence of liver function
impairments with atorvastatin was not high compared with other similar drugs.
However, some patients in the clinical studies of atorvastatin were withdrawn from the
study due to liver function impairment. Furthermore, in overseas countries, when
subjects with normal liver function and cirrhosis patients received oral repeated dose of
10mg of atorvastatin once daily for 14 days, patients with mild cirrhosis in the category
A of Child-Pugh Classification showed a 5.5 times increase in Cmax and a 4.4 times
increase in AUC0-24hr and patients with moderate cirrhosis in the category B of Child-
Pugh Classification showed a 14.4 times increase in Cmax and a 9.8 times increase in
AUC0-24hr (it has been reported that AUC of the control drug pravastatin in cirrhosis
patients with unknown severities was 1.34 times of normal subjects). Therefore, the
Evaluation Centre instructed the Applicant to make a modification of the Precautions for
Use in patients with hepatic impairments. We would like to hear from the Subcommittee
whether the narratives in the Precautions for Use are satisfactory.
Indications, Dosage and Administration Method:
The cholesterol lowering effect of atorvastatin was demonstrated in clinical studies in
hypercholesterolemia patients excluding homozygotic familial hypercholesterolemia
patients. The efficacy of 10mg atorvastatin was supported by significant decreases in TC
and LDL-C compared with the control drug of 10mg pravastatin. However, TC and
LDL-C lowering effects were observed at a dose level of 2.5mg and the incidence of
adverse events seemed to be correlated with the dosed amount. Therefore, we would
like to hear the Subcommittee’s opinion on appropriateness of selecting 10mg as the
optimum dose. We also would like to hear the Subcommittee’s opinion on
appropriateness of the maximum dose, 40mg.
In the atorvastatin clinical program, hyperlipidemia patients were recruited, but the
inclusion criteria did not specify TG levels, though it specified TC levels. In the clinical
program, nine patients in the phase IIa studies, 12 patients in the phase IIb study and 26
patients in phase III study had fluctuations of TG levels within ±10% and over 150mg/dL
during the observation period. As well as hypertriglyceridemia patients, many patients
who only had raised TC were included in the placebo-controlled phase IIa study.
However, the active drug groups showed a significant lowering effect than the placebo,
though there was no difference in the 5mg, 10mg and 50mg groups and no clear dose-
response was observed. In the phase III study, stratified analysis was carried out in
hypertriglyceridemia patients and atorvastatin’s TG lowering effect was observed in
comparison with the control drug. Therefore, the TG lowering effect was thought to be
present, even though the mode of action was unknown. Nevertheless, the reduction rate
was lower than fibrates. We would like to hear the Subcommittee’s opinion on
approvability with an indication for hyperlipidemia including hypertriglyceridemia.
RESULTS FROM A RELIABILITY CHECK BY THE KIKO AND
INTERPRETATION BY THE EVALUATION CENTER
1) Interpretation of the reliability check result by the Evaluation Centre
(Organization for Pharmaceutical Safety and Research) carried out an audit on
documents as stipulated in the last paragraph of Section 4, Article 14 of the
Pharmaceutical Affairs Law. There were some incompatibilities (e.g. there were some
protocol violations in clinical results, expressions used in the approval application
document did not reflect the source document correctly). However, the Evaluation
Centre considered that the audit result would not cause an impediment in carrying out an
evaluation based on the approval evaluation data.
2) Interpretation of the GCP audit result by the Evaluation Centre
In the GCP audit, it had come to light that patients included in a late phase IIb study
were also included in a phase III study. The patients were excluded from the evaluation
data. There were no other issues and the Evaluation Centre considered that the audit
result would not cause an impediment in carrying out an evaluation based on the
4. OVERALL ASSESSMENT OF THE EVALUATION CENTRE
Subject to confirmation of the following points with the Subcommittee, the Evaluation
Centre has no objection in approving the filed drug.
5) Indication: should it be hyperlipidemia including hypertriglyceridemia?
6) Appropriateness of the optimum dose of 10mg and the maximum dose of
7) Confirmation of Precautions for Use for hepatic impaired patients
SUMMARY OF SUBCOMMITTEE DISCUSSION
Based on the document submitted, we do not have objections in approving the drug, as
long as the indications are amended and the chairperson verifies responses to the
instructions for the Evaluation Centre.
2. REPORT FROM THE SUBCOMMITTEE
Regarding toxicity studies, the Subcommittee requested the Evaluation Centre for details
of a mechanism of “hepatocellular variations” which were observed in the 52-week oral
dose toxicity study in rats. Hepatocyte hypertrophy was a typical hepatocellular
variation and it was considered to be a morphological change due to enzyme inductions.
Unlike in rats, HMG-CoA reductase inhibitors did not induce these enzymes in humans
and the Evaluation Centre believed such a change would not happen in humans. The
hepatocellular variations observed with administration of atorvastatin were not
progressive and the degree was reduced with time. Furthermore, as atorvastatin
carcinogenicity studies in rats showed all negative oncogenecity, the Evaluation Centre
explained that the hepatocellular variations were not associated with formation of
neoplasia. The response was accepted.
The Evaluation Centre was asked to review liver toxicity of atorvastatin using a rat liver
disease model. The Evaluation Centre argued that a toxicity assessment using a rat liver
disease model was not widely accepted as a method of predicting undesirable effect of a
drug in humans with hepatopathy. They also stated that the incidence of GOT and GPT
elevations above fivefold of the normal value was 0.1% in the Japanese clinical studies
and there was no significant difference in reports of hepatopathy with atorvastatin
compared with other agents. The responses were accepted. To address this matter, the
Important Basic Precautions in the Precautions for Use refers to a need for regular liver
The Evaluation Centre had argued that the hepatocarcinogenicity in mice was a result of
a promoter activity of atorvastatin. The Subcommittee asked for the rationale of the
argument. The Evaluation Centre replied that even though they mentioned the promoter
actions as a mode of mechanism of carcinogenicity, no findings supported this theory.
The Evaluation Centre explained that the mechanisms of the increase in hepatocellular
tumour was unknown because atorvastatin did not show genotoxicity and there was no
difference in cell proliferation activities compared with the control group when PCNA
was used as index. However, the dose at which carcinogenicity was seen in mice
differed largely from the clinical dose. Also, there was no report suggesting tumour
inductions in the clinical use of HMG-CoA reductase inhibitors. Therefore, the
Evaluation Centre believed that the atorvastatin had a low carcinogenic potential. The
The Subcommittee requested a review on the reduction of spermatid in the testis, which
was observed in the 100mg/kg group of the rat oral feed-mix reproductive study. The
Evaluation Centre replied that, in a gavage oral dose reproductive study, no effect on the
reproductive function, male reproductive organs and sperm parameters was observed.
The Subcommittee requested the Evaluation Centre to re-examine the reduction of
spermatid in the testis, which might be an effect of atorvastatin. The Evaluation Centre
replied that no effect on the spermatid count in the testis was observed in the gavage oral
dose study. In addition, the Evaluation Centre submitted results of an already
implemented 104-week oral dose toxicity study in beagles because the effect of some
HMG-CoA reductase inhibitors on the testis were observed in repeat-dose studies in
dogs. They explained that test results from Week 52 to Week 91 did not show
significant changes due to atorvastatin. Also abnormalities in sperm test data observed
with 104 weeks administration of 120mg/kg, which reduced blood cholesterol levels to
about 50% of the control group, were not considered to be biologically significant
changes. However, the Subcommittee insisted on the study to be repeated because the
existing study did not evaluate the effect of reduced blood cholesterol levels on
With regard to malformation and mutation observed in the oral dose organogenesis study
in rabbits, the Subcommittee asked for a justification of the no toxicity dose in dams and
foetuses because one of the rationales for ruling out a relevancy to atorvastatin was not
acceptable (malformation and mutation were limited to dams with poor foetal growth).
The Evaluation Centre amended the no toxicity dose for dams and foetuses to 10mg/kg
because death, body weight gain suppression, abortion in dams and foetal bodyweight
reduction and an increase in the embryonic death rate after nidation were observed at
The Subcommittee also asked the Evaluation Centre to provide a discussion on a trend
of increase in the incidence of pyelectasis in the 225mg/kg group, which was observed in
the organogenesis, peri- and postnatal oral study in rats. The Evaluation Centre
explained that this was associated with atorvastatin because it was higher than the
control group, although within a range of background data for the rats used in the study.
Descriptions in the Contraindications in the Precautions for Use and the Administration
to Pregnant, Parturient and Nursing Women were amended to address this matter.
With regard to absorption, distribution, metabolism and excretion, the Subcommittee
requested the Evaluation Centre to describe causes of the low (around 10%) atorvastatin
bioavailability (BA) in human and experimental animals. The Evaluation Centre was
instructed to explain absorption processes at the digestive tract and the first pass effect
separately. They replied that the absorption rate of atorvastatin at the digestive tract was
considered to be about 60 to 70% in both humans and animals and the differences from
BA were due to the first pass effect. Even though atorvastatin was mainly eliminated via
the liver, a presence of metabolism in the digestive tract was qualitatively demonstrated
in a metabolism experiment with human enterocyte microsome. The Evaluation Centre
explained that metabolisms in the digestive tract as well as in the liver were involved
because atorvastatin was metabolised by CYP3A4. The Subcommittee accepted the
explanations. Furthermore, the Subcommittee asked for an explanation of a tendency of
AUC to increase more than the dose ratio when the dose was increased in a human
repeated oral dose study. The Evaluation Centre explained that this was due to one
subject in 20mg who showed high AUC by chance and they demonstrated that the
average increase without this subject was roughly proportional to the dosed amount.
With regard to the TC lowering effect of atorvastatin, the Subcommittee asked for a
justification of the indication of hyperlipidemia, considering the fact that TG was not a
primary endpoint in the atorvastatin clinical studies and the number of patients in the
efficacy evaluation (with TG levels of above 150mg/dL as well as the TG fluctuations
within ±10% in more than two serum lipids measurements during the observation period)
was extremely low. The Evaluation Centre argued that various lipid parameters
including TG levels were the primary endpoints in studies with an exception of the phase
III comparative study. A significant TG Lowering effect compared with placebo was
observed in the phase IIa study. They also indicated that TG was assessed as a secondly
endpoint in the phase III comparative study and the study showed a trend of TG
reduction by atorvastatin compared with pravastatin, although it varied. Furthermore,
they expressed their opinion that dose dependent TG lowering effect was confirmed in
overseas studies in hypertriglyceridaemia patients and the atorvastatin should be
indicated for hyperlipidemia. However, the Subcommittee instructed that the indication
should be “hypercholesterolemia” because they believed that insufficient data for
demonstrating clinical usefulness were available.
The Subcommittee requested the Evaluation Centre to compare the LDL lowering effect
and the inhibitory effect on VLDL secretion of atorvastatin with similar drugs and give a
logical discussion using data from studies which directly supported a pharmacokinetic
justification and findings from past papers. The Evaluation Centre expressed their
opinion that the lipid lowering effect was associated with 1) more selective and durable
up-take to the liver, 2) stronger activities of the main metabolite with comparable plasma
metabolite AUC to the parent-form, 3) a more durable effect due to longer plasma half-
life of the parent-form and the main metabolite, compared with other drugs. With regard
to the inhibitory effect on VLDL secretion, they suggested that because the half-life of
atorvastatin was longer than other drugs, cholesterol synthesis activities were inhibited
for longer, which led to a more pronounced inhibitory effect on VLDL secretion and
expression of the serum TG lowering effect. They also argued that, at the same time that
the LDL supply was reduced as expected from the inhibitory effect on VLDL secretion,
the LDL lowering effect was enhanced by the induction of the LDL receptor activities,
which led to the stronger blood LDL lowering effect. The Subcommittee accepted the
replies. With regard to the clinical significance of TG reduction, the Evaluation Centre
explained that a direct proof of the clinical significance had not been obtained, though
suppression of development of ischemic heart diseases and arteriosclerotic diseases,
which were reported in fibrates, would be expected considering the TG lowering effect
With regard to the high incidences of abnormal changes in lab test results, the
Subcommittee requested a description of possible drug interactions with concomitant
drugs. The Evaluation Centre replied that direct effect from concomitant drugs was
relatively small compared with effect from concurrent disorder, etc. The Subcommittee
accepted the response. The Evaluation Centre explained the higher incidence of
testosterone reductions in females was not a sex difference due to the pharmacological
actions of atorvastatin. There was no effect on serum testosterone concentrations in
general pharmacology studies and there was no finding that suggested the presence of
direct inhibitions of testosterone biosynthesis in the repeated oral dose studies.
Therefore, the Evaluation Centre argued that the possibilities of atorvastatin to directly
inhibit testosterone biosynthesis within the clinical dose range were low. Furthermore,
with regard to a possibility of interactions via CYP, the Evaluation Centre stated that a
possibility of enzyme inductions leading to the acceleration of testosterone metabolism
was minimal because the main drug metabolising P450 in humans were not included in
testosterone biosynthesis enzymes and atorvastatin did not induce the atorvastatin
metabolising enzyme CYP3A4. The Subcommittee accepted those responses.
The Evaluation Centre was instructed to provide an explanation on drug interactions of
atorvastatin with SU preparations and oral contraceptives. They replied that they were
unable to pinpoint obvious interactions with SU preparations. When oral estradiol or
estriol were used concomitantly with atorvastatin, there was a possibility of their plasma
concentrations increasing, involving metabolism inhibition by atorvastatin at the digestive
tract. Also, a main component of bonding oestrogen was converted into estrone and
metabolised by CYP3A4, hence estrone plasma concentrations might increase.
Therefore, oral contraceptives were also added in the Drug Interactions of the
Results up to 52 weeks of the long-term study were submitted, integrating already
In 311 hypercholesterolemia patients, changes in various serum lipid levels during a 52-
week administration of 10mg of atorvastatin once daily after evening meals were almost
constant after Week 4 till Week 52. The rates of normalisation of TC and LDL-C were
82.9% and 86.6% respectively. The incidences of adverse drug reactions and clinical test
abnormal changes that may be relevant to atorvastatin based on data up to Week 26 were
9.4% and 40.1% and those based on data up to Week 52 were 11.8% and 41.5%,
respectively. Common events were raised liver enzymes, CPK, glucose and HbAlc and
reduced testosterone. These results were the same as the results obtained in other
clinical studies of atorvastatin. No doubt over efficacy and safety was suggested in long-
Discussion items which were pointed out by the Evaluation Centre:
1) Appropriateness of indication of hyperlipidemia including hypertriglyceridemia:
The indication should be hypercholesterolemia because hypercholesterolemia
patients were targeted in the clinical program and the number of TG patients
included in the efficacy analysis was minimal and data obtained were insufficient
for demonstrating clinical usefulness.
2) Appropriateness of the optimum dose of 10mg and the maximum dose of 40mg:
10mg is appropriate as a dose level which is safe and provides maximum effect.
In familial hypercholesterolemia patients, a reduction in cholesterol outweighs
minor adverse drug reactions. Therefore, it is necessary to use the maximum
3) Precautions for Use for hepatic impaired patients are appropriate.
As a consequence of the above discussions, the Subcommittee reached a conclusion that
the filed drug was approvable. Therefore, the articles are going to be brought forward to
The drug substance and the drug products are not classified as Powerful Drug.
EVALUATION SUMMARY (PART 2)
Pharmaceuticals and Medical Device Evaluation Centre
1. SUMMARY OF EVALUATION FOLLOWING THE FIRST
With regard to stability, additional results of long-term storage studies were submitted.
In the long-term storage study (36 months), no changes in the drug substance were
observed after storage and the drug substance was stable for three years at the ambient
In the long-term storage study (24 months), few changes in the drug products were
observed and the drug products were stable for 24 months at the ambient temperature.
The long-term storage study of the drug products is still on-going.
In relation to the effect of atorvastatin on the reduction of the testis sperm cell counts in
the feed-mix reproductive study, the effect of low blood cholesterol levels caused by the
efficacy of atorvastatin on the reproductive potentials of male animals, etc., was not
assessed. The Applicant promised that they would investigate its effect on male
reproductive potential using animal species that had blood cholesterol reductions.
The Evaluation Centre requested the Applicant to supply a justification on the use of rats
in the female fertility study because, in general, HMG-CoA reductase inhibitors were
known not to lower blood cholesterol concentrations of rats. The Applicant responded
that a female fertility study was usually carried out in rats or mice and these animals were
used in female fertility studies of other HMG-CoA reductase inhibitors. The applicant
believed that they had completed assessment of reproductive and developmental
toxicities of atorvastatin and the metabolites, except for the issues related to blood
cholesterol reductions. They explained that the biggest concern with regard to blood
cholesterol reduction and reproductive and developmental toxicities was teratogenicity,
but the organogenesis study in rabbits with any of the HMG-CoA reductase inhibitors
did not show an induction of holoprosencephaly. The Applicant believed that HMG-
CoA reductase inhibitors including atorvastatin would not reduce human blood
cholesterol levels to the levels observed in patients with Smith-Lemli-Opitz Syndromes
and a possibility of inducing malformation associated with hypocholesterolemia in clinical
practice was minimal. Although atorvastatin was not likely to induce malformations due
to hypocholesterolemia in clinical practice, the Applicant suggested implementing a study
in order to investigate the effect of induced hypocholesterol on reproductive potential in
male and female animals and development of early embryo. The Evaluation Centre
Referring to the international prescribing information and the US labels, atorvastatin was
contraindicated to breast-feeding women. Narratives of reductions in a number of
offspring and effect on their survival and development, which were observed in animal
experiments, and occurrences of congenital malformations with other HMG-CoA
reductase inhibitors were added to the prescribing information under the section of
Administration to Pregnant, Childbearing and Breastfeeding Women. The Evaluation
Centre considered the amendments appropriate.
The Evaluation Centre believes the amendment of indication from “hyperlipidemia” to
“hypercholesterolemia” is appropriate.
2. CONCLUSION OF EVALUATION
In conclusion of evaluation carried out at the Evaluation Centre and the Second
Subcommittee Meeting on New Drug, the Evaluation Centre has no objection in granting
EVALUATION SUMMARY (PART 3)
Pharmaceuticals and Medical Device Evaluation Centre
The phrase “if further effect is required” in relation to a dose increase in the Dosage and
Administration Method was not appropriate. The Evaluation Centre believed that this
should be replaced with “in severe cases” and instructed the Applicant to amend the
EVALUATION REPORT (PART 2)
Product Name: Lipitor, Lipitor 5mg Tablet, Lipitor 10mg Tablet
Generic Name: Atorvastatin calcium hydrate
24th August 1998 (Import approval of the drug substance,
manufacturing approval of the drug product)
Drug product: Yamanouchi Pharmaceutical Co., Ltd
During the discussion in the First Special Committee Meeting on Drugs of the
Pharmaceutical Affairs Council, the committee pointed out that the calculated numeric
data in the pharmacological investigation of the clinical dose against the effective dose
were estimates and they should not have been used in a comparison. Therefore, relevant
sentences concerning pharmacological actions in the Gaiyo
(Part 1, page 5, lines 15 to
This amendment will not affect the conclusion of the evaluation.
Iniciativa climática e florestal do governo norueguês O aquecimento global é talvez um dos principais desafios de nossos tempos e uma das tarefas mais árduas que a comunidade internacional tem enfrentado até hoje. A Noruega tem como meta prioritária limitar o aumento da temperatura média global a 2 graus em relação ao nível pré-industrial. De acordo com o Painel Intergo
U.S. Department of Justice United States Attorney Northern District of Illinois ─────────────────────────────────────────────────────────── Zachary T. Fardon Everett McKinley Dirksen Federal Courthouse TEXAS HONEY BROKER SENTENCED TO THREE YEARS IN PRISON FOR AVO