Leaflet Silliver Tabs

Size: 144 x 134mm

Date: 11-07-2015, 13-07-2015
Ammara Commercial Printers (Pvt.) Ltd.

Laboratory values such as SGOT, SGPT and GLDH were clearly lower on the
first post-operative day for the treated group as compared with the control
patients. This absence of extreme enzymatic changes was attributed to
Silymarin activity.

INDICATIONS
SILLIVER (Silymarin) is indicated as adjunctive therapy in the treatment of
liver disease of varying etiologies; acute hepatitis, chronic persistent and
chronic aggressive hepatitis, cirrhosis of liver, fatty liver, toxic metabolic or
toxic metabolic liver damage. It has been shown to protect the liver from
damage caused by general anesthesia.
ADVERSE REACTIONS
SILLIVER (Silymarin) is normally well-tolerated, even when the physician
intends to administer it over long periods of time. At high doses, a slight laxative
and diuretic effect may be observed.
CONTRAINDICATIONS
SILLIVER (Silymarin) is contraindicated in individuals with a hypersensitivity to
the product, or when mechanical obstacles are present in the biliary tracts.
PRECAUTIONS
No conditions have been encountered which would preclude the administration
of SILLIVER (Silymarin).
PRODUCT NAME
SILLIVER (Silymarin)
List numbers: E181
DESCRIPTION
SILLIVER (Silymarin). A yellow-brown microgranular powder, is a mixture of
natural products isolated from the fruits of the milk thistle. Silybum marianum
(L) Gaertn. The major component, Silybin (silybum substance E) is identified
chemically as 2-[2,3-Dihydro-2-(4-hydroxy-3-methoxyphenyl]-3-
(hydroxymethyl)-1,4-benzodfoxin-6-y1] 2,3-dihydro-3,5,7-trihydroxy- 4H-
1-benzopyran-4-one-the major component of the group.
SILLIVER (Silymarin) is insoluble in water but soluble in certain organic
solvents.

PREGNANCEY AND LACTATION COMPOSITION

SILLIVER (Silymarin) has not been reported to alter normal pregnancy, and Each Silliver tablet contains:
there has been no evidence of embryo toxicity. There is no evidence of impaired Silymarin abbott specs. ......... 200mg.
development of the breast-fed infant.
CLINICAL PHARMACOLOGY
DRUG INTERACTIONS The exact mechanism by which SILLIVER (Silymarin) protects the liver is not
Reactions between SILLIVER (Silymarin) and other medications have not been known. It has been postulated that the drug acts by stabilizing liver cell
reported. membranes, thereby reducing their permeability to certain toxic substances.
This stabilization may occur as the result of competitive inhibition between
DOSAGE AND ADMINISTRATION SILLIVER (Silymarin) and hepatotoxic substances at the level of the cell
Adults: Except when the physician directs otherwise, it is recommended to membrane.
initiate treatment with 200 mg twice a day. After 4-6 weeks, the dosage may
be reduced to 200 mg once a day. The results of pharmacological testing indicate that SILLIVER (Silymarin)
protects liver cells from damage induced by agents (alcohol, carbon
Children: One-half of the adult dosage. tetrachloride, general anesthetics) known to have destructive effects on liver
cells. Published clinical data demonstrate that SILLIVER (Silymarin) is safe,
The therapy may be continued over long periods of time. and well tolerated. When administered as adjunctive therapy to patients with a
variety of liver disease, SILLIVER (Silymarin) improves clinical and biochemical
HOW SUPPLIED parameter.
SILLIVER (Silymarin) is supplied as 200mg tablets in amber glass bottles of 15's
& 30's in carton. List number E181. PRE-CLINICAL PHARMACOLOGY
1. Silymarin has been reported to reverse the liver damage produced by carbon
STORAGE : tetrachloride (CCI4) poisoning in the rat. Electron microscopy shows
Protect from heat, light & moisture. structural normalization of hepatocyte mitochondria and endoplasmic
Keep out of the reach of children. reticula after administration of Silymarin. Concomitantly, there are
increases in hepatic ATP, diamino-oxidase, lactic acid and glycogen.
Silymarin prevents CCI4 - induced increases of lactic and pyruvic acids,
gastric acid and pepsin secretions and serum levels of SGOT, SGPT, SDH,
GLDH and free fatty acids.

2. Silymarin shows pharmacologic activity in the hexobarbital-induced sleep

model. Animals pre-treated with Silymarin have an overall sleep time less
than those who receive carbon tetrachloride only, but higher than unrelated
animals. These data indicate that administration of Silymarin prior to receipt
of CCI4 improves liver function as evidenced by enhanced metabolism of
hexobarbital.

3. The frequently-fatal sequelae of mushroom poisoning are, in large part, the

results of severe liver and kidney damage caused by alpha-amanitine and
phalloidine, toxins which inhibit protein synthesis. The death rate from
01-141R2 alpha-amanitine and phalloidine is reduced in mice and rats by administering
IMDS00861001 12-JUL-2001
 Silymarin before or after administration of the toxin. The curative effect
appears to be time-dependent, i.e. It is increased substantially if the time
interval between intoxication and therapy is less than 20 minutes.
4. After treatment with Silymarin, levels of triglyceride in the liver of ethanol-
treated animals are markedly reduced. Moreover, ethanol-induced
mitochondrial changes are minimized by administration of Silymarin.
5. Chronic administration of thioacetamide to rats produces a histological
cirrhosis, similar to that seen in human beings; long-term administration
results in weight loss and death of the animals. Concomitant administration
of Silymarin prolongs survival time, attenuates weight loss and normalizes
the elevated SGOT, SGPT, SDH and GLDH due to thioacetamide
poisoning.
6. Silymarin is effective in reducing the elevated serum SGOT, SGPT and
GLDH values induced by galactosamine in the rat.
7. Administration of Silymarin before and after 1% halothane anesthesia
prevents the appearance of fatty liver.
8. Silymarin is effective in reducing elevated SGOT, SGPT, SOH and GLDH
levels induced by praseodymium, a rare-earth metal.
9. Mice treated with Silymarin and exposed to total body irradiation show less
weight loss, faster recovery and increased survival rate when compared with
untreated mice.
10. Administration of Silymarin is reported to increase the mitotic regeneration
in liver cells of rats after partial hepatectomy. Hepatic regeneration in the
treated rats was better than in untreated controls.
TOXICOLOGY
The acute oral and intravenous toxicity of Silymarin has been determined in
several species. No signs of toxicity were seen in the mouse after 20g/kg p.o., or
in the dog after 1 g/kg p.o. There were no signs of toxicity in the rat after doses of
130 mg/kg I.V. for 7 days. The following LD50 were obtained for mice and rats;
Female Male
Mouse 1050 mg/kg 970 mg/kg
Rat 825 mg/kg 920 mg/kg
The MLD (minimum lethal dose) for the rabbit was about 300 mg/kg; the
tolerance limit in the dog was about 300 mg/kg. These values show the low
toxicity of Silymarin.
Sub-chronic toxicity studies in the rat showed no side effects at doses of 1 g/kg
p.o. for 15 days. The same results were observed in chronic toxicity tests of 16
and 22 weeks. A long-term trial in beagle dogs also revealed no toxicity.
Detailed clinical, chemical and histological examinations showed no indication
of pathological changes.
CLINICAL STUDIES
There are some 1250 published cases describing the clinical use of Silymarin.
These reports deal with the treatment of patients with acute and chronic
hepatitis, Cirrhosis of the liver, and toxic-metabolic liver damage including fatty
infiltration of liver. Several controlled studies are summarized below:
1 Two groups of patients considered homogenous with regard to subjective
and objective clinical symptoms and laboratory parameters were studied.
The treated group was composed of 18 patients who received 70 mg
Silymarin 3 times daily for 15 days; the control group consisted of 16 patients
who received no treatment for 15 days. After 15 days, significant clinical
improvement (p < 0.01) was noted in the group treated with Silymarin when
compared with untreated controls.
Following the 15-day controlled trial, both groups were put on the same
treatment schedule consisting of oral Silymarin, plus levulose 5% or dextrose
5% I.V. the dosage of Silymarin ranged from 210-420 mg/day and duration of
treatment was 21 to 41 days. A statistically significant decrease (p<0.01)
between pre-and post-treatment values was seen in BUN, bilirubin, alkaline
phosphatase, SGOT and SGPT. No side effects or adverse reactions that could
be attributed to Silymarin were observed during the entire study. These data
indicate that Silymarin is effective and well- tolerated in patients with
decompensated liver disease.
2. One hundred twenty-nine patients with toxic or toxic metabolic liver
disease such as fatty liver, chronic hepatitis and post-hepatitic syndrome
were treated with Silymarin (210 mg/day for 5 weeks); 56 patients with
similar hepatic diseases were used as controls. Treatment with Silymarin
resulted in improvement in clinical symptoms and liver function tests,
particularly BSP and transaminase values; untreated patients showed a
slight, but not significant, clinical improvement. Silymarin was well -
tolerated and no side effects were observed, elicited or reported.
3. Forty patients with toxic-metabolic liver disease due to alcohol, diabetes or
exogenous poisons were treated with Silymarin (210-420 mg/day for 7
weeks). The clinical picture of treated patients improved markedly when
compared to 30 control cases who received their customary liver-
protecting regimen. Highly significant reductions in SGOT, SGPT, BSP,
serum iron, cholesterol and alkaline phosphatase were observed in the
treated groups. In many treated patients, there was a correlation between
normalization of blood chemistry and histological findings. In the control
group, a significant decrease was seen in bilirubin, SGOT and SGPT only.
4. Thirty patients with chronic diffuse hepatic disease were included in this
study. Fifteen patients received 4.20 mg of Silymarin per day and 15
patients served as controls. Improvement of liver function tests was
observed in patients treated with Silymarin when compared with untreated
controls.
5. The hepatoprotective effect of Silymarin following anesthesia and surgery
was studied in 5 patients undergoing surgical procedures (70%
cholecystectomy and 30% vagotomy associated with pyloroplasty). Fifteen
patients were divided into 3 groups of 5 patients each: Group A received
2.5% pentothal and 0.5 to 2.5% enflurane; Group B received 1-4%
enflurane; Group C was treated the same as Group B, but the patients also
received Silymarin 150 mg for II days (3 consecutive days before surgery
and 8 consecutive days after surgery).
Analysis of these 3 groups showed fewer biochemical and histological changes
in Group C than in Groups A and B. In Group A, electron microscopy revealed
alterations in mitochondria and slight changes in endoplasmic reticulum.
Moreover, post-surgical values for total bilirubin showed a significant increase
from the pre-surgical values. In Group B, there was a significant increase of
thymol turbidity. Light microscopy revealed changes in hepatic structure
evidenced by loosening of the parenchyma; electron microscopy showed
disorganization of the endoplasmic reticulum. In Group C, There was significant
decrease from control values for direct, indirect and total bilirubin. These
variations were interpreted as an improvement of liver function induced by
Silymarin. No changes in the hepatic structure in Group C were noted with
either light or electron microscopy. There were not reported, observed or
elicited side effects from Silymarin in any group tested.
6. The effect of Silymarin on changes during the pre-and post operative period
was studied in 31 patients. The daily dose of Silymarin was 420 mg
administered for 10-14 days. Treatment was initiated 2-4 days before
surgery and continued for 8 days thereafter; 32 patients were used as
controls. Anesthesia was induced with hexobarbital and suxamethonium,
followed by continuous inhalation of oxygen and halothane.