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SUPRALIP 160 FILM-COATED TABLETS

Active substance(s): FENOFIBRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Supralip® 160 mg, film-coated tablet.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 160.0 mg fenofibrate.
Excipients with known effect: each tablet contains:
-

138.4 mg of Lactose monohydrate

0.56 mg of Soybean lecithin.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film coated tablet.
White, oblong, film-coated tablets engraved “160” on one side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Supralip® 160mg is indicated as an adjunct to diet and other non-pharmacological
treatment (e.g. exercise, weight reduction) for the following:
- Treatment of severe hypertriglyceridaemia with or without low HDL cholesterol.
- Mixed hyperlipidaemia when a statin is contraindicated or not tolerated.
- Mixed hyperlipidaemia in patients at high cardiovascular risk in addition to a statin
when triglycerides and HDL cholesterol are not adequately controlled.

4.2

Posology and method of administration
Dietary measures initiated before therapy should be continued. Response to therapy
should be monitored by determination of serum lipid values. If an adequate response
has not been achieved after several months, complementary or different therapeutic
measures should be considered.
Posology:

Adults:
The recommended dose is one tablet containing 160 mg fenofibrate taken once daily.
Patients currently taking one Lipantil Micro 200mg capsule can be changed to one
Supralip 160 mg tablet without further dose adjustment.
Special populations
Elderly patients (≥ 65 years old)
No dose adjustment is necessary. The usual dose is recommended, except for
decreased renal function with estimated glomerular filtration rate < 60 mL/min/1.73
(see Patients with renal impairment).
Patients with renal impairment
Fenofibrate should not be used if severe renal impairment, defined as eGFR <30
mL/min per 1.73 m2, is present.
If eGFR is between 30 and 59 mL/min per 1.73 m2, the dose of fenofibrate should not
exceed 100 mg standard or 67 mg micronized once daily.
If, during follow-up, the eGFR decreases persistently to <30 mL/min per 1.73 m2,
fenofibrate should be discontinued.
Hepatic impairment:
Supralip 160 mg is not recommended for use in patients with hepatic impairment due
to the lack of data.
Paediatric population:
The safety and efficacy of fenofibrate in children and adolescents younger than 18
years has not been established. No data are available. Therefore the use of fenofibrate
is not recommended in paediatric subjects under 18 years.
Method of administration:
Tablet should be swallowed whole during a meal.

4.3

Contraindications







Hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver
function abnormality)
Known gallbladder disease
Severe renal insufficiency (estimated glomerular filtration rate < 30 mL/min/1.73
m2)
Chronic or acute pancreatitis with the exception of acute pancreatitis due to
severe hypertriglyceridemia
Known photoallergy or phototoxic reaction during treatment with fibrates or
ketoprofen,
Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1.

In addition, Supralip 160 mg should not be taken in patients allergic to peanut or
arachis oil or soya lecithin or related products due to the risk of hypersensitivity
reactions.

4.4

Special warnings and precautions for use
Secondary causes of hyperlipidemia:
Secondary cause of hypercholesterolemia, such as uncontrolled type 2 diabetes
mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver
disease or alcoholism should be adequately treated before fenofibrate therapy is
considered. Secondary cause of hypercholesterolemia related to pharmacological
treatment can be seen with diuretics, β-blocking agents, estrogens, progestogens,
combined oral contraceptives, immunosuppressive agents and protease inhibitors. In
these cases it should be ascertained whether the hyperlipidaemia is of primary or
secondary nature (possible elevation of lipid values caused by these therapeutic
agents).
Liver function:
As with other lipid lowering agents, increases have been reported in transaminase
levels in some patients. In the majority of cases these elevations were transient, minor
and asymptomatic. It is recommended that transaminase levels are monitored every 3
months during the first 12 months of treatment and thereafter periodically. Attention
should be paid to patients who develop increase in transaminase levels and therapy
should be discontinued if AST (SGOT) and ALT (SGPT) levels increase to more than
3 times the upper limit of the normal range. When symptoms indicative of hepatitis
occur (e.g. jaundice, pruritus), and diagnosis is confirmed by laboratory testing,
fenofibrate therapy should be discontinued.
Pancreas:
Pancreatitis has been reported in patients taking fenofibrate (see sections
Contraindications and Undesirable effects). This occurrence may represent a failure
of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a
secondary phenomenon mediated through biliary tract stone or sludge formation with
obstruction of the common bile duct.
Muscle:
Muscle toxicity, including rare cases of rhabdomyolysis, with or without renal failure,
has been reported with administration of fibrates and other lipid-lowering agents. The
incidence of this disorder increases in case of hypoalbuminaemia and previous renal
insufficiency. Patients with pre-disposing factors for myopathy and/or
rhabdomyolysis, including age above 70 years, personal or familial history of
hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol
intake, may be at an increased risk of developing rhabdomyolysis. For these patients,
the putative benefits and risks of fenofibrate therapy should be carefully weighed up.
Muscle toxicity should be suspected in patients presenting diffuse myalgia, myositis,
muscular cramps and weakness and/or marked increases in CPK (levels exceeding 5
times the upper normal range). In such cases treatment with fenofibrate should be
stopped.
The risk of muscle toxicity may be increased if the drug is administered with another
fibrate or an HMG-CoA reductase inhibitor, especially in case of pre-existing
muscular disease. Consequently, the co-prescription of fenofibrate with HMG-CoA
reductase inhibitor or another fibrate should be reserved to patients with severe
combined dyslipidaemia and high cardiovascular risk without any history of muscular
disease and with a close monitoring of potential muscle toxicity.

Renal function:
Supralip 160 mg is contraindicated in severe renal impairment (see section 4.3).
Supralip 160 mg should be used with caution in patients with mild to moderate renal
insufficiency. Dose should be adjusted in patients whose estimated glomerular
filtration rate is 30 to 59 mL/min/1.73 m2 (see section 4.2).
Reversible elevations in serum creatinine have been reported in patients receiving
fenofibrate monotherapy or co-administered with statins. Elevations in serum
creatinine were generally stable over time with no evidence for continued increases in
serum creatinine with long term therapy and tended to return to baseline following
discontinuation of treatment.
During clinical trials, 10% of patients had a creatinine increase from baseline greater
than 30 μmol/L with co-administered fenofibrate and simvastatin versus 4.4% with
statin monotherapy. 0.3% of patients receiving co-administration had clinically
relevant increases in creatinine to values > 200 μmol/L.
Treatment should be interrupted when creatinine level is 50% above the upper limit
of normal. It is recommended that creatinine is measured during the first 3 months
after initiation of treatment and periodically thereafter.
Excipients:
As this medicinal product contains lactose, therefore patients with rare hereditary
problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
Oral anticoagulants:
Fenofibrate enhances oral anticoagulant effect and may increase risk of
bleeding. It is recommended that the dose of anticoagulants is reduced by
about one third at the start of treatment and then gradually adjusted if
necessary according to INR (International Normalised Ratio) monitoring.
Cyclosporin:
Some severe cases of reversible renal function impairment have been reported
during concomitant administration of fenofibrate and cyclosporin. The renal
function of these patients must therefore be closely monitored and the
treatment with fenofibrate stopped in the case of severe alteration of laboratory
parameters.
HMG-CoA reductase inhibitors and other fibrates:
The risk of serious muscle toxicity is increased if a fibrate is used
concomitantly with HMG-CoA reductase inhibitors or other fibrates. Such
combination therapy should be used with caution and patients monitored
closely for signs of muscle toxicity (See section 4.4 Special warnings and
precautions for use).
Glitazones:

Some cases of reversible paradoxical reduction of HDL-cholesterol have been
reported during concomitant administration of fenofibrate and glitazones.
Therefore, it is recommended to monitor HDL-cholesterol if one of these
components is added to the other and stopping of either therapy if HDLcholesterol is too low.
Cytochrome P450 enzymes:
In vitro studies using human liver microsomes indicate that fenofibrate and
fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms
CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of
CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at
therapeutic concentrations.
Patients co-administered fenofibrate and CYP2C19, CYP2A6, and especially
CYP2C9 metabolised drugs with a narrow therapeutic index should be
carefully monitored and, if necessary, dose adjustment of these drugs is
recommended.

4.6

Fertility, pregnancy and lactation
Pregnancy: There are no adequate data from the use of fenofibrate in pregnant
women. Animal studies have not demonstrated any teratogenic effects. Embryotoxic
effects have been shown at doses in the range of maternal toxicity (see section 5.3
Preclinical safety data). The potential risk for humans is unknown. Therefore,
Supralip 160 mg film-coated tablet should only be used during pregnancy after a
careful benefit/risk assessment.
Lactation: It is unknown whether fenofibrate and/or its metabolites are excreted in
human milk. A risk to the suckling child cannot be excluded. Therefore fenofibrate
should not be used during breast-feeding.
Fertility: Reversible effects on fertility have been observed in animals (see section
5.3). There are no clinical data on fertility from the use of Supralip 160 mg.

4.7

Effects on ability to drive and use machines
Supralip 160 mg has no or negligible influence on the ability to drive and use
machines.

4.8

Undesirable effects
The most commonly reported ADRs during fenofibrate therapy are digestive, gastric
or intestinal disorders. The following undesirable effects have been observed during
placebo-controlled clinical trials (n=2344) and post-marketinga with the below
indicated frequencies:

MedDRA system
organ class

Common
≥1/100, <1/10

Uncommon ≥1/1,000,
<1/100

Rare ≥1/10,000,
<1/1,000

Very rare
<1/10,000 incl.
isolated reports

Haemoglobin
decreased
White blood cell
count decreased

Blood and
lymphatic system
disorders
Immune system
disorders
Nervous system
disorders

Hypersensitivity
Headache
Thromboembolism
(pulmonary embolism,
deep vein thrombosis)*

Vascular
disorders
Respiratory,
thoracic and
mediastinal
disorders

Gastrointestinal
disorders

Hepatobiliary
disorders

Skin and
subcutaneous
tissue disorders

Musculoskeletal,
connective tissue
and bone
disorders
Reproductive
system and breast
disorders
General disorders
and
administration
site conditions

Frequency
unknowna (cannot
be estimated from
the available data)

Interstitial lung
diseasea
Gastrointestinal
signs and
symptoms
(abdominal pain,
nausea, vomiting,
diarrhoea,
flatulence)
Transaminases
increased
(see section 4.4)

Pancreatitis*

Cholelithiasis (see
section 4.4)

Cutaneous
hypersensitivity (e.g.
rash, pruritus,
urticaria)

Hepatitis

Alopecia
Photosensitivity
reactions

Muscle disorder (e.g.
myalgia, myositis,
muscular spasms and
weakness)

Jaundice,
complications of
cholelithiasis a
(e.g. cholecystitis,
cholangitis, biliary
colic)
Severe cutaneous
reactionsa (e.g
erythema
multiforme,
Stevens-Johnson
syndrome, toxic
epidermal
necrolysis)
Rhabdomyolysisa

Sexual dysfunction

Fatiguea

Blood
Blood creatinine
Blood urea
homocysteine
increased
increased
level increased**
In the FIELD-study, a randomized placebo-controlled trial performed in 9,795 patients with type 2 diabetes
mellitus, a statistically significant increase in pancreatitis cases was observed in patients receiving fenofibrate
versus patients receiving placebo (0.8% versus 0.5%; p = 0.031). In the same study, a statistically significant
increase was reported in the incidence of pulmonary embolism (0.7% in the placebo group versus 1.1% in the
fenofibrate group; p = 0.022) and a statistically non-significant increase in deep vein thromboses (placebo:
1.0% [48/4,900 patients] versus fenofibrate 1.4% [67/4,895 patients];
p = 0.074).

Investigations
*

** In the FIELD-study, the average increase in blood homocysteine level in patients treated with fenofibrate was
6.5 µmol/L, and was reversible on discontinuation of fenofibrate treatment. The increased risk of venous

thrombotic events may be related to the increased homocysteine level. The clinical significance of this is not
clear.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Only anecdotal cases of fenofibrate overdosage have been received. In the majority of
cases no overdose symptoms were reported.
No specific antidote is known. If an overdose is suspected, treat symptomatically and
institute appropriate supportive measures as required. Fenofibrate cannot be
eliminated by haemodialysis.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Serum Lipid Reducing Agents / Cholesterol and Triglycerides Reducers /
Fibrates.
ATC code: C10 AB 05
Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in
humans are mediated via activation of Peroxisome Proliferator Activated Receptor
type alpha (PPARα).
Through activation of PPARα, fenofibrate increases the lipolysis and elimination of
atherogenic triglyceride-rich particles from plasma by activating lipoprotein lipase
and reducing production of apoprotein CIII. Activation of PPARα also induces an
increase in the synthesis of apoproteins AI and AII.
The above stated effects of fenofibrate on lipoproteins lead to a reduction in very lowand low density fractions (VLDL and LDL) containing apoprotein B and an increase
in the high density lipoprotein fraction (HDL) containing apoprotein AI and AII.
In addition, through modulation of the synthesis and the catabolism of VLDL
fractions fenofibrate increases the LDL clearance and reduces small dense LDL, the
levels of which are elevated in the atherogenic lipoprotein phenotype, a common
disorder in patients at risk for coronary heart disease.
During clinical trials with fenofibrate, total cholesterol was reduced by 20 to 25%,
triglycerides by 40 to 55% and HDL cholesterol was increased by 10 to 30%.
In hypercholesterolaemic patients, where LDL cholesterol levels are reduced by 20 to
35%, the overall effect on cholesterol results in a decrease in the ratios of total
cholesterol to HDL cholesterol, LDL cholesterol to HDL cholesterol, or Apo B to
Apo AI, all of which are markers of atherogenic risk.

There is evidence that treatment with fibrates may reduce coronary heart disease
events but they have not been shown to decrease all cause mortality in the primary or
secondary prevention of cardiovascular disease.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was a
randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus
treated with fenofibrate in addition to simvastatin. Fenofibrate plus simvastatin
therapy did not show any significant differences compared to simvastatin
monotherapy in the composite primary outcome of non-fatal myocardial infarction,
non-fatal stroke, and cardiovascular death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08,
p = 0.32; absolute risk reduction: 0.74%). In the pre-specified subgroup of
dyslipidaemic patients, defined as those in the lowest tertile of HDL-C (≤34 mg/dl or
0.88 mmol/L) and highest tertile of TG (≥204 mg/dl or 2.3 mmol/L) at baseline,
fenofibrate plus simvastatin therapy demonstrated a 31% relative reduction compared
to simvastatin monotherapy for the composite primary outcome (hazard ratio [HR]
0.69, 95% CI 0.49-0.97, p = 0.03 ; absolute risk reduction: 4.95%). Another
prespecified subgroup analysis identified a statistically significant treatment-bygender interaction (p = 0.01) indicating a possible treatment benefit of combination
therapy in men (p=0.037) but a potentially higher risk for the primary outcome in
women treated with combination therapy compared to simvastatin monotherapy
(p=0.069). This was not observed in the aforementioned subgroup of patients with
dyslipidaemia but there was also no clear evidence of benefit in dyslipidaemic women
treated with fenofibrate plus simvastatin, and a possible harmful effect in this
subgroup could not be excluded.
Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be
markedly reduced or even entirely eliminated during fenofibrate therapy.
Patients with raised levels of fibrinogen treated with fenofibrate have shown
significant reductions in this parameter, as have those with raised levels of Lp(a).
Other inflammatory markers such as C Reactive Protein are reduced with fenofibrate
treatment.
The uricosuric effect of fenofibrate leading to reduction in uric acid levels of
approximately 25% should be of additional benefit in those dyslipidaemic patients
with hyperuricaemia.
Fenofibrate has been shown to possess an anti-aggregatory effect on platelets in
animals and in a clinical study, which showed a reduction in platelet aggregation
induced by ADP, arachidonic acid and epinephrine.

5.2

Pharmacokinetic properties
Supralip 160 mg is a film-coated tablet containing 160 mg of micronised
fenofibrate and is suprabioavailable (larger bioavailability) compared to the
previous formulations.
Absorption:
Maximum plasma concentrations (Cmax) occur within 4 to 5 hours after oral
administration. Plasma concentrations are stable during continuous treatment
in any given individual.

The absorption of fenofibrate is increased when administered with food.
Distribution:
Fenofibric acid is strongly bound to plasma albumin (more than 99%).
Metabolism and excretion:
After oral administration, fenofibrate is rapidly hydrolysed by esterases to the
active metabolite fenofibric acid. No unchanged fenofibrate can be detected in
the plasma. Fenofibrate is not a substrate for CYP 3A4. No hepatic
microsomal metabolism is involved.
The drug is excreted mainly in the urine. Practically all the drug is eliminated
within 6 days. Fenofibrate is mainly excreted in the form of fenofibric acid
and its glucuronide conjugate. In elderly patients, the fenofibric acid apparent
total plasma clearance is not modified.
Kinetic studies following the administration of a single dose and continuous
treatment have demonstrated that the drug does not accumulate. Fenofibric
acid is not eliminated by haemodialysis.
The plasma elimination half-life of fenofibric acid is approximately 20 hours.

5.3

Preclinical safety data
In a three-month oral nonclinical study in the rat species with fenofibric acid, the
active metabolite of fenofibrate, toxicity for the skeletal muscles (particularly those
rich in type I -slow oxidative- myofibres) and cardiac degeneration, anemia and
decreased body weight were seen. No skeletal toxicity was noted at doses up to 30
mg/kg (approximately 17-time the exposure at the human maximum recommended
dose (MRHD). No sign of cardiomyotoxicity were noted at an exposure about 3 times
the exposure at MRHD. Reversible ulcers and erosions in the gastro-intestinal tract
occurred in dogs treated for 3 months. No gastro-intestinal lesions were noted in that
study at an exposure approximately 5 times the exposure at the MRHD.
Studies on mutagenicity of fenofibrate have been negative.
In rats and mice, liver tumours have been found at high dosages, which are
attributable to peroxisome proliferation. These changes are specific to small rodents
and have not been observed in other animal species. This is of no relevance to
therapeutic use in man.
Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic
effects were observed at doses in the range of maternal toxicity. Prolongation of the
gestation period and difficulties during delivery were observed at high doses.
Reversible hypospermia and testicular vacuolation and immaturity of the ovaries were
observed in a repeat-dose toxicity study with fenofibric acid in young dogs. However
no effects on fertility were detected in non-clinical reproductive toxicity studies
conducted with fenofibrate.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium laurilsulfate

Lactose monohydrate
Povidone
Crospovidone
Microcrystalline cellulose
Silica colloidal anhydrous
Sodium stearyl fumarate
Composition of the coating:
Opadry®:
- polyvinyl alcohol
- titanium dioxide (E171)
- talc
- soybean lecithin
- xanthan gum.

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years.

6.4

Special precautions for storage
Store in the original package in order to protect from moisture.
Do not store above 30°C.

6.5

Nature and contents of container
Thermoformed blister strips (PVC/PE/PVDC sealed with aluminium comples)
of 10 or 14 tablets each.
Boxes of 10, 20, 28, 30, 50, 84, 90, 98 and 100 tablets.
Hospital pack sizes: 280 (10 x 28) and 300 (10 x 30) tablets.
Not all pack sizes may be marketed

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Mylan Products Ltd.
20 Station Close
Potters Bar
Herts
EN6 1TL
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 46302/0024

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
11/09/2008

10

DATE OF REVISION OF THE TEXT
10/02/2017

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