This information is intended for use by health professionals

1. Name of the medicinal product

Ciprofibrate 100mg Tablets

2. Qualitative and quantitative composition

Each tablet contains 100mg ciprofibrate as the active ingredient.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

White to Off White capsule shaped tablet plain on one side and break line on other side.

The break line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical particulars
4.1 Therapeutic indications

Ciprofibrate tablets are 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.

4.2 Posology and method of administration

Posology

Adults

The recommended dosage is one tablet (100mg ciprofibrate) per day. This dose should not be exceeded (see Precautions).

Elderly Patients

As for adults, but see Precautions and Warnings.

Use in Case of Impaired Renal Function

In moderate renal impairment (creatinine clearance 30-80 ml/min/1.73m2) it is recommended that dosage be reduced to one tablet every other day. Patients should be carefully monitored. Ciprofibrate should not be used in severe renal impairment (creatinine clearance <30 ml/min/1.73m2).

Use in Children

Not recommended since safety and efficacy in children has not been established.

Method of administration

For oral use.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section6.1.

Severe hepatic impairment.

Severe renal impairment (creatinine clearance <30 ml/min/1.73m2).

Pregnancy and lactation, or when pregnancy is suspected.

Concurrent use with another fibrate.

Previous phototoxicity caused by fibrates

4.4 Special warnings and precautions for use

Special warnings

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

Myalgia/myopathy:

Patients should be advised to report unexplained muscle pain, tenderness or weakness immediately.

CPK levels should be assessed immediately in patients reporting these symptoms. Therapy should be discontinued if myopathy is diagnosed or if markedly elevated CPK levels (levels exceeding 5 times the normal range) occur.

Doses of 200mg ciprofibrate per day or greater have been associated with a high risk of rhabdomyolysis. Therefore the daily dose should not exceed 100mg.

The risk of myopathy may be increased in the presence of the following predisposing factors:

• impaired renal function and any situation of hypoalbuminaemia such as nephrotic syndrome

• hypothyroidism or untreated hypothyroidism

• alcohol abuse

• age > 70 years

• personal or family history of hereditary muscular disorders

• previous history of muscular toxicity with another fibrate

As with other fibrates, the risk of rhabdomyolysis and myoglobinuria may be increased if ciprofibrate is used in combination with other fibrates or HMG CoA reductase inhibitors (see sections 4.3 and 4.5).

Use with caution in patients with impaired hepatic function.

Periodic hepatic function tests are recommended (every 3 months for the first 12 months of treatment). Ciprofibrate treatment should be discontinued in case of increased AST and ALT levels to more than 3 times the upper limit of normal or if cholestatic liver injury is evidenced.

Secondary causes of dyslipidaemia, such as hypothyroidism, should be excluded or corrected prior to commencing any lipid lowering drug treatment.

In patients with hypertriglyceridaemia, ciprofibrate may cause an increase of the LDL level

Special precautions for use

Association with oral anticoagulant therapy: concomitant oral anticoagulant therapy should be given at reduced dosage and adjusted according to INR (see section 4.5).

If after a period of administration lasting several months, a satisfactory reduction in serum lipid concentrations has not been obtained, additional or different therapeutic measures must be considered.

4.5 Interaction with other medicinal products and other forms of interaction

Other fibrates: As with other fibrates, the risk of rhabdomyolysis and myoglobinuria may be increased if ciprofibrate is used in combination with other fibrates (see sections 4.3 and 4.4.).

Not recommended combinations

HMG CoA reductase inhibitors: As with other fibrates, the risk of myopathy, rhabdomyolysis and myoglobinuria may be increased if ciprofibrate is used in combination with HMG CoA reductase inhibitors (see section 4.4). The benefits of combined use should be carefully weighed against the risks. Physicians contemplating concomitant therapy with HMG CoA reductase inhibitors should consult the SPC of the relevant HMG CoA reductase inhibitor as some higher doses are contraindicated / not recommended with fibrates.

Combination requiring caution

Oral anticoagulant therapy: Ciprofibrate is highly protein bound and therefore likely to displace other drugs from plasma protein binding sites. This may increase the effects of drugs like phenytoin, tolbutamide and other sulphonylurea derivatives and coumarin-like anticoagulants. Ciprofibrate has been shown to potentiate the effect of warfarin, indicating that concomitant oral anticoagulant therapy should be given at reduced dosage and adjusted according to INR (see section 4.4).

Combination to be taken into account

Cholestyramine and colestipol may reduce the absorption of ciprofibrate. These drugs should not be taken together or close to each other.

No clinically relevant interactions exist with cytochrome P450, beta blocking agents, calcium antagonists, diuretics, other hypertensives digoxin and nitroglycerin

Oral hypoglycaemics: Although ciprofibrate may potentiate the effect of oral hypoglycaemics, available data do not suggest that such an interaction may be clinically significant.

Oestrogens: Oestrogens can raise lipid levels. Although a pharmacodynamic interaction may be suggested, no clinical data are currently available.

4.6 Fertility, pregnancy and lactation

Fertility

There are no data on the effects of ciprofibrate on fertility in humans.

Pregnancy

There are insufficient data from the use of ciprofibrate in pregnant women. Animal studies have demonstrated neonatal thrombosis (see section 5.3). The potential risk for humans is unknown. Ciprofibrate is contraindicated during pregnancy (see section 4.3)

Lactation

Ciprofibrate is contraindicated during breast-feeding (see section 4.3). It is not known if ciprofibrate is excreted into breast milk.

4.7 Effects on ability to drive and use machines

Dizziness, somnolence, and fatigue have only rarely been reported in association with ciprofibrate. Patients should be warned that if they are affected they should not drive or operate machinery.

4.8 Undesirable effects

Cutaneous disorders:

Cutaneous reactions mainly allergic have been reported: rashes, urticaria, pruritus and eczema, and very rarely photosensitivity.

As with other drugs in this class, a low occurrence of alopecia has been reported.

Muscular disorders:

As with other fibrates, elevation of serum creatine phosphokinase (CPK), myalgia and myopathy including myositis and rare cases of rhabdomyolysis have been reported. In the majority of cases muscle toxicity is reversible when treatment is withdrawn (see section 4.4).

Neurological disorders:

Occasional reports of headache, vertigo.

Dizziness, somnolence have only rarely been reported in association with ciprofibrate.

As with other drugs of this class, a low occurrence of impotence has been reported.

Gastro-intestinal disorders:

There have been occasional reports of gastrointestinal symptoms including nausea, vomiting, diarrhoea, dyspepsia, and abdominal pain. Generally, these side effects were mild to moderate in nature and occurred early on, becoming less frequent as treatment progressed.

Hepato-biliary disorders:

As with other fibrates, abnormal hepatic function tests have been observed occasionally. Very rare cases of cholestasis or cytolysis have been reported (see section 4.4). Exceptional cases with chronic evolution have been observed. Some cases of cholelithiasis have been reported.

Pulmonary disorders:

Isolated cases of pneumonitis or pulmonary fibrosis have been reported.

General disorders:

Fatigue has only rarely been reported in association with ciprofibrate.

Blood and Lymphatic System Disorders

Leukocytopenia has been described once. Thrombocytopenia – Frequency not known

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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms

Overdosage with ciprofibrate has been rarely reported. Some cases of overdose are known, but in these cases, no adverse reactions specific to overdose have been observed. In the worst case, after ingestion of 2800 mg ciprofibrate for 3 days, rhabdomyolysis observed.

Treatment

There are no specific antidotes to ciprofibrate. Treatment of overdosage should be symptomatic. The usual measures should be taken to prevent further absorption of the drug from the gastro-intestinal tract. Gastric lavage and appropriate supportive care may be instituted if necessary. Ciprofibrate is non-dialysable.

5. Pharmacological properties
5.1 Pharmacodynamic properties

ATC Code: C10A B08

Pharmacotherapeutic group: Serum lipid reducing agents - fibrates.

Ciprofibrate is a new derivative of phenoxyisobutyric acid which has a marked hypolipidaemic action. It reduces both LDL and VLDL and hence the levels of triglyceride and cholesterol associated with these lipoprotein fractions. It also increases levels of HDL cholesterol. The mechanism of action of ciprofibrate is not entirely clear. It includes increased VLDL catabolism, but may also be influenced by reduced synthesis of VLDL or direct effect on the LDL receptor

Ciprofibrate is effective in the treatment of hyperlipidaemia associated with high plasma concentrations of LDL and VLDL (types IIa, IIb, III and IV according to the Fredrickson Classification). In clinical studies ciprofibrate has been shown to be effective in complementing the dietary treatment of such conditions.

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.

5.2 Pharmacokinetic properties

Ciprofibrate is readily absorbed in man, with maximum plasma concentrations occurring mainly between one and four hours following an oral dose. Following a single dose of 100mg, in volunteers, maximum plasma concentration of ciprofibrate was between 21 and 36μg/ml. In patients on chronic therapy, maximum levels from 53 to 165μg/ml have been measured. The plasma protein binding of ciprofibrate is about 98% in the therapeutic range.

Terminal elimination half-life in patients on long term therapy varies from 38 to 86 hours. The elimination half-life in subjects with moderate renal insufficiency was slightly increased compared with normal subjects (116.7h compared with 81.1h). In subjects with severe renal impairment, a significant increase was noted (171.9h).

Approximately 30-75% of a single dose administered to volunteers was excreted in the urine in 72 hours, either as unchanged ciprofibrate (20-25% of the total excreted) or as a conjugate. Subjects with moderate renal impairment excreted on average 7.0% of a single dose as unchanged ciprofibrate over 96 hours, compared with 6.9% in normal subjects. In subjects with severe insufficiency this was reduced to 4.7%.

5.3 Preclinical safety data

In animal studies with respect to reproduction neonatal thrombosis is seen in rats at doses similar to the therapeutic dosage. The potential risk for humans is unknown.

Other findings add nothing to the clinical experience.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose Monohydrate

Hydroxypropyl methyl cellulose

Sodium Lauril Sulphate

Purified water

Microcrystalline cellulose

Maize Starch

Powdered Vegetable Stearing/Hydrogenated vegetable oil

6.2 Incompatibilities

Not applicable

6.3 Shelf life

PVC/Aluminium Blister pack: 3 Years

Aluminium/Aluminium Blister pack: 3 Years

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package to protect from moisture.

6.5 Nature and contents of container

Tablets are packed in clear/transparent PVC/Aluminium or Aluminium/Aluminium blisters containing 28 Tablets.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Focus Pharmaceuticals Limited

Capital House

85 King William Street

London

EC4N 7BL

UK

8. Marketing authorisation number(s)

PL 20046/0298

9. Date of first authorisation/renewal of the authorisation

05/04/2013

10. Date of revision of the text

06/01/2016