Supralip 160 mg Film-coated Tablets

Summary of Product Characteristics Updated 28-Apr-2017 | Mylan

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 HDL-cholesterol 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 160mg, Film-coated tablet 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:

Frequency
Very rare unknowna
MedDRA system Common Uncommon Rare ≥1/10,000, (cannot be
<1/10,000 incl.
organ class ≥1/100, <1/10 ≥1/1,000, <1/100 <1/1,000 estimated from
isolated reports
the available
data)

Haemoglobin
Blood and decreased
lymphatic system
disorders White blood cell
count decreased

Immune system
Hypersensitivity
disorders

Nervous system
Headache
disorders

Thromboembolism
(pulmonary
Vascular disorders
embolism, deep vein
thrombosis)*

Respiratory,
Interstitial lung
thoracic and
mediastinal diseasea
disorders

Gastrointestinal
signs and
symptoms
Gastrointestinal (abdominal pain,
Pancreatitis*
disorders nausea,
vomiting,
diarrhoea,
flatulence)

Jaundice,
Transaminases complications of
Hepatobiliary Cholelithiasis (see cholelithiasis a
increased Hepatitis
disorders section 4.4) (e.g. cholecystitis,
(see section 4.4) cholangitis, biliary
colic)

Severe cutaneous
reactionsa (e.g
Cutaneous Alopecia erythema
Skin and
hypersensitivity (e.g. multiforme,
subcutaneous Photosensitivity
rash, pruritus, Stevens-Johnson
tissue disorders reactions
urticaria) syndrome, toxic
epidermal
necrolysis)

Musculoskeletal, Muscle disorder (e.g.

connective tissue myalgia, myositis, Rhabdomyolysisa
and bone muscular spasms
disorders and weakness)

Reproductive Sexual dysfunction

system and breast
 disorders

General disorders
and administration Fatiguea
site conditions

Blood
Blood creatinine Blood urea
Investigations 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).
** 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 low- and 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-by-
gender 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) 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 and other handling

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
Date of first authorisation: September 2000
Date of last renewal: 4 November 2004
10. Date of revision of the text
10 February 2017
11. Legal category
POM
Company Contact Details
Mylan
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