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LIPANTIL MICRO 67 MG CAPSULES

Active substance(s): FENOFIBRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

2

NAME OF THE MEDICINAL PRODUCT

Lipantil® Micro 67 mg, capsules.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 67 mg fenofibrate.
Excipients with known effect: each capsule contains:
- 33.8 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Yellow, hard gelatin capsule.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Lipantil® Micro 67mg is indicated as an adjunct to diet and other nonpharmacological 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 (e.g. 3 months), complementary or
different therapeutic measures should be considered.
Posology:
Adults:

The recommended dose is 200mg daily administered as three capsules of Lipantil
Micro 67mg.
The dose can be titrated up to 267mg daily administered as 4 capsules of Lipantil
Micro 67mg, if required. This maximum dose is not recommended in addition to a
statin.
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:
Lipantil Micro 67mg is not recommended for use in patients with hepatic impairment
due to the lack of data.
Paediatric population:
In children, the recommended dose is one capsule (67mg) micronised fenofibrate /
day / 20kg body weight (see section 4.4).
Method of administration:
Capsules 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.

4.4

Special warnings and precautions for use
Secondary causes of hyperlipidemia:
Secondary causes of hyperlipidemia, such as uncontrolled type 2 diabetes mellitus,
hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease,
pharmacological treatment, 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 4.3 and 4.8).
This occurrence may represent a failure of efficacy in patients with severe
hypertriglyceridaemia, 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 cases 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 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 cases of pre-existing
muscular disease. Consequently, the co-prescription of fenofibrate with a 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 a close monitoring of potential muscle toxicity.
Renal function:
Lipantil Micro 67 mg is contraindicated in severe renal impairment (see section 4.3).

Lipantil Micro 67 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, patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
should not take this medicine.
In children:
Only an hereditary disease (familial hyperlipidaemia) justifies early treatment, and
the precise nature of the hyperlipidaemia must be determined by genetic and
laboratory investigations. It is recommended to begin treatment with controlled
dietary restrictions for a period of at least 3 months. Proceeding to medicinal
treatment should only be considered after specialist advice and only in severe forms
with clinical signs of atherosclerosis and/or xanthomata and/or in cases where
patients suffer from atherosclerotic cardiovascular disease before the age of 40.

4.5

Interaction with other medicinal products and other forms of interaction
Oral anti-coagulants
Fenofibrate enhances oral anti-coagulant effect and may increase risk of bleeding. In
patients receiving oral anti-coagulant therapy, the dose of anti-coagulant should be
reduced by about one-third at the commencement of treatment and then gradually
adjusted if necessary according to INR (International Normalised Ratio) monitoring.
HMG-CoA reductase inhibitors or 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).
There is currently no evidence to suggest that fenofibrate affects the
pharmacokinetics of simvastatin.
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.
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 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.
Other
In common with other fibrates, fenofibrate induces microsomal mixed-function
oxidases involved in fatty acid metabolism in rodents and may interact with drugs
metabolised by these enzymes.

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).
The potential risk for humans is unknown.
Therefore, Lipantil Micro 67mg 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 Lipantil Micro 67 mg.

4.7

Effects on ability to drive and use machines
Lipantil® Micro 67mg has no or negligible influence on the ability to drive and
use machines.

4.8

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

MedDRA
system organ
class

Common
>1/100, <1/10

Uncommon
>1/1,000, <1/100

Blood and
lymphatic
system disorders

Haemoglobin
decreased
White blood cell
count decreased
Hypersensitivity

Immune system
disorders
Nervous system
disorders
Vascular
disorders

Gastrointestinal
disorders

Hepatobiliary
disorders

Headache

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

Skin and
subcutaneous
tissue disorders
Musculoskeletal,
connective
tissue and bone
disorders
Reproductive
system and
breast disorders
Investigations

Rare
>1/10,000,
<1/1,000

Blood

Thromboembolism
(pulmonary
embolism, deep
vein thrombosis)*
Pancreatitis*

Cholelithiasis (see
section 4.4)

Hepatitis

Cutaneous
hypersensitivity
(e.g. Rashes,
pruritus, urticaria)
Muscle disorder
(e.g. myalgia,
myositis, muscular
spasms and
weakness)
Sexual dysfunction

Alopecia
Photosensitivity
reactions

Blood creatinine

Blood urea

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

homocysteine
level
increased**

increased

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.

In addition to those events reported during clinical trials, the following side effects
have been reported spontaneously during postmarketing use of Lipantil. A precise
frequency cannot be estimated from the available data and is therefore classified as
“not known”.
− Respiratory, thoracic and mediastinal disorders: Interstitial lung disease.
− Musculoskeletal, connective tissue and bone disorders: Rhabdomyolysis.
− Hepatobiliary disorders: jaundice, complications of cholelithiasis (e.g.
cholecystitis, cholangitis, biliary colic)
− Skin and Subcutaneous Tissue Disorders: severe cutaneous reactions (e.g
erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)
− General disorders and administration site conditions: Fatigue
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 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 Triglyceride Reducers/Fibrates. ATC
code:C10 AB 05.
Lipantil Micro 67 is a formulation containing 67mg of micronised fenofibrate.

Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in
humans are mediated via activation of Peroxisome Proliferator Activated Receptor
type α (PPARα). Through activation of PPARα, fenofibrate increases lipolysis and
elimination of atherogenic triglyceride rich particles from plasma by activating
lipoprotein lipase and reducing production of Apoprotein C-III. Activation of
PPARα also induces an increase in the synthesis of Apoproteins A-I and A-II.
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.
Studies with fenofibrate consistently show decreases in levels of LDL-cholesterol.
HDL-cholesterol levels are frequently increased. Triglyceride levels are also reduced.
This results in a decrease in the ratio of low and very low density lipoproteins to high
density lipoproteins, which has been correlated with a decrease in atherogenic risk in
epidemiological studies. Apolipoprotein-A and apolipoprotein-B levels are altered in
parallel with HDL and LDL and VLDL levels respectively.
Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be
markedly reduced or even entirely eliminated during fenofibrate therapy.
Plasma uric acid levels are increased in approximately 20% of hyperlipidaemic
patients, particularly in those with type IV phenotype.

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.
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.
Limited paediatric data are available. The effects of fenofibrate in dyslipidemic
children have been studied in two small clinical trials and in an open long-term
surveillance registry with 76 hypercholesterolemic children aged 3 to 18 years
receiving fenofibrate for 1 to 11 years. However, due to limited data and
methodological insufficiencies, no definitive conclusion can be drawn on the use of
fenofibrate in dyslipidemic children.
Adverse events similar to those observed in adults have been reported in children:
leucopenia, liver function test abnormal, rhabdomyolysis, renal failure, hepatitis,
jaundice, myositis and rhabdomyolysis.

5.2

Pharmacokinetic properties
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 hydrolised 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 glucuronoconjugate.

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 during 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, anaemia 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 signs 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 the 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
Excipients: lactose monohydrate, magnesium stearate, pregelatinised starch,
sodium laurilsulfate, crospovidone.
Composition of the capsule shell: gelatin, titanium dioxide (E171), quinoline
yellow (E104) and erythrosine (E127).

6.2

Incompatibilities
No effect noted to date.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Store in the original package. Do not store above 30oC.

6.5

Nature and contents of container
Pack of 28,56,84,90 capsules in blisters (PVC/Aluminium).
*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 46302/0044

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
03/07/2007

10

DATE OF REVISION OF THE TEXT
10/02/2017

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