Summary of medicine characteristics - Pelzont
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each modified-release tablet contains 1,000 mg of nicotinic acid and 20 mg of laropiprant.
Excipient(s) with known effect:
Each modified-release tablet contains 128.4 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Modified-release tablet.
Capsule-shaped, white to off-white tablet, with “552” debossed on one side.
4.
4.1
Pelzont is indicated for the treatment of dyslipidaemia, particularly in adult patients with combined mixed dyslipidaemia (characterised by elevated levels of LDL-cholesterol and triglycerides and low HDL-cholesterol) and in adult patients with primary hypercholesterolaemia (heterozygous familial and non-familial).
Pelzont should be used in patients in combination with HMG-CoA reductase inhibitors (statins), when the cholesterol lowering effect of HMG-CoA reductase inhibitor monotherapy is inadequate. It can be used as monotherapy only in patients in whom HMG-CoA reductase inhibitors are considered inappropriate or not tolerated. Diet and other non-pharmacological treatments (e.g. exercise, weight reduction) should be continued during therapy with Pelzont.
4.2 Posology and me
f administration
Posology
The starting dose is one modified-release tablet (1,000 mg nicotinic acid/20 mg laropiprant) once a day. After four weeks, it is recommended that patients be advanced to the maintenance dose of 2,000 mg/40 mg taken as two modified-release tablets (1,000 mg/20 mg each) once daily. Daily doses greater than 2,000 mg/40 mg have not been studied and therefore are not recommended.
If Pelzont is missed for less than 7 consecutive days, patients can resume therapy at the last administered dose. If Pelzont is missed for 7 or more consecutive days, therapy should be resumed at the 1,000 mg/20 mg dose for 1 week, before advancing to the maintenance dose of 2,000 mg/40 mg.
Those patients switching from 2,000 mg or more of prolonged-release nicotinic acid can initiate Pelzont at the 2,000 mg/40 mg dose. Patients switching from less than 2,000 mg of prolonged-release nicotinic acid should initiate therapy at the starting dose of 1,000 mg/20 mg and advance to the 2,000 mg/40 mg maintenance dose after four weeks. For patients switching from immediate-release nicotinic acid to Pelzont, therapy should be initiated at the 1,000 mg/20 mg dose and advanced to the 2,000 mg/40 mg maintenance dose after four weeks.
Elderly patients
No dose adjustment is required for elderly patients.
Paediatric population
Safety and effectiveness of Pelzont in paediatric patients under the age of 18 years have not been established. No data are available.
Patients with hepatic or renal insufficiency
Use of Pelzont in patients with hepatic or renal insufficiency has not been studied. Like other nicotinic acid medicinal products, Pelzont is contraindicated in patients with significant or unexplained hepatic dysfunction. It should be used with caution in patients with renal insufficiency, because nicotinic acid and its metabolites are primarily excreted by the kidneys (see sections 4.3, 4.4 and 5.2).
Concomitant therapy
Acetylsalicylic acid provides no additional reduction of flushing beyond that achieved by Pelzont. Therefore, treatment with acetylsalicylic acid to alleviate flushing symptoms is not necessary (see section 5.1).
Because co-administration of bile acid sequestrants may reduce the bioavailab lity of acidic medicinal products such as nicotinic acid, it is recommended that Pelzont be administered > 1 hour before or > 4 hours after administration of a bile acid sequestrant (see section 4.5).
Method of administration
The tablets should be taken whole, with food, in the evening or at bedtime. To preserve the modified-release properties, the tablets must not be split, broken, crushed, or chewed before swallowing. To reduce the possibility of flushing, drinking alcohol or hot drinks or eating spicy foods should be avoided at the time of ingestion of the medicinal product.
4.3
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Significant or unexplained hepatic dysfunction.
Active peptic ulcer disease.
Arterial bleeding.
4.4
4- t < r ví, a ď • i j. ,i.1, r c. r z>^4.5 Interaction with other medicinal products and other forms of interaction
Acetylsalicylic acid: In a clinical study, concomitant administration of laropiprant with acetylsalicylic acid did not have an effect on collagen-induced platelet aggregation or on bleeding time compared to treatment with acetylsalicylic acid alone (see section 5.1).
Acetylsalicylic acid and clopidogrel: In a clinical study in dyslipidaemic patients receiving both acetylsalicylic acid (81 mg) and clopidogrel (75 mg), laropiprant induced transient (4 hours post-dose) inhibition of platelet function in vivo (as evaluated by bleedin time and platelet aggregation studies), but had little effect across the dosing interval. Patients receiving Pelzont concomitantly with acetylsalicylic acid and clopidogrel should be closely monitored as recommended in the Summary of Product Characteristics for those medicinal products and should be told that it might take longer than usual to stop bleeding and that they should report any unusual bleeding (site or duration) to their physician.
Effects of other medicinal products on laropiprant
CYP3A4 Inhibitor: Clarithromycin (a potent inhibitor of CYP3A4 and P-gp) did not have a clinically meaningful effect on the pharmacokinetics of laropiprant. Laropiprant is not a substrate of human P-gp, and therefore other inhibitors of CYP3A4 and/or P-gp are also not expected to have a clinically meaningful impact on the pharmacokinetics of laropiprant.
4.6 Fertility, pregnancy and lactation
Pregnancy
Pelzont
There are no data from the combined use of nicotinic acid and laropiprant in pregnant women. The combination has not been tested in reproductive toxicity studies. The potential risk for humans is unknown. Therefore, Pelzont should not be used during pregnancy unless clearly necessary.
Nicotinic acid
There are no adequate data from the use of high dose nicotinic acid in pregnant women. Studies in animals have shown foetal developmental toxicity at high doses of nicotinic acid (see section 5.3).
Laropiprant
There are no data from the use of laropiprant in pregnant women. Studies in animals have shown foetal developmental toxicity at high doses of laropiprant (see section 5.3).
Breast-feeding
Pelzont
No studies in lactating animals have been conducted with Pelzont. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy should be made taking into account the benefit of breast-feeding to the child and the benefit of Pelzont to the woman.
Nicotinic acid
Nicotinic acid is excreted in human breast milk.
Laropiprant
It is unknown whether laropiprant is excreted in human breast milk. Animal studies have shown excretion of laropiprant in milk.
Fertility
Animal studies are insufficient with respect to impairment on fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
When driving vehicles or operating machines, it should be taken into account that dizziness has been reported (see section 4.8).
4.8 Undesirable effects
In clinical trials, over 5,700 patients received Pelzont alone or with an HMG-CoA reductase inhibitor.
Summary of the safety profile
Flushing is the most common adverse reaction of Pelzont. Flushing is most prominent in the head, neck, and upper torso. In a pool of four active- or placebo-controlled clinical trials (N=4,747, n=2,548 taking Pelzont), flushing was reported in 12.3 % of patients taking Pelzont. In these studies, the
percentage of patients taking Pelzont, nicotinic acid (pooled prolonged-release formulations) or pooled placebo/simvastatin who discontinued due to any flushing-related symptom (redness, warmth, itching respectively.
and tingling) was 7.2 %, 16.6 %, and 0.4 % Tabulated list of adverse reactions <O
The following adverse reactio with Pelzont (with or without
een reported during clinical studies and/or post-marketing use
The frequencies of adverse reactions are ranked according to the following: Very common (> 1/10), Common (> 1/100 to < 1/10), Uncommon (> 1/1,000 to < 1/100), Rare (> 1/10,000 to < 1/1,000), Very rare (< 1/10,000), Not known (cannot be estimated from the available data).
| System organ class | Adverse reaction |
| Infections and infestations | Rare : rhinitis |
| Immune system disorders | Uncommon : hypersensitivity reaction (see below) Rare : angio-oedema; type I hypersensitivity Not known : anaphylactic shock |
| Metabolism and nutrition disorders | Uncommon : gout Rare : impaired glucose tolerance |
| Psychiatric disorders | Uncommon : insomnia Rare : anxiety |
| Nervous system disorders | Common : headache; paraesthesia Uncommon : dizziness Rare : migraine; syncope |
| Cardiac disorders | Uncommon : palpitations Rare : atrial fibrillation and other cardiac arrhythmias; tachycardia |
| System organ class | Adverse reaction |
| Vascular disorders | Very common : flushing Uncommon : hypotension Rare : orthostatic hypotension |
| Respiratory, thoracic, and mediastinal disorders | Uncommon : dyspnoea |
| Gastrointestinal disorders | Common : abdominal pain; diarrhoea; dyspepsia; nausea; vomiting Rare : mouth oedema; eructation; peptic ulcer |
| Hepatobiliary disorders | Not known : jaundice |
| Skin and subcutaneous tissue disorders | Common: erythema; pruritus; rash; urticaria Uncommon : dry skin; macular rash Rare : acanthosis nigricans; hyperpigmentation; sweating (night or cold sweat) Not known : vesicular or vesiculobullous rash |
| Musculoskeletal and connective tissue disorders | Uncommon : myalgia Rare : muscular weakness < |
| General disorders and administration site conditions | Common : feeling hot Uncommon : chills; pain; peripheral oedema Rare : asthaenia; face oedema; generalisedJosdcma |
| Investigations | Common : elevations in ALT and/or ASTJconsecutive, > 3 X ULN), fasting glucose (see below) Uncommon : elevations in CK (>10^ULN), LDH, uric acid (see below) XZ- Rare: elevations in total bilirubin, amylase; reductions in phosphorus and platelet counts (see below) |
Hypersensitivity reactions
An apparent hypersensitivity reaction has been reported (< 1 %). This is characterised by multiple symptoms that may include: angio-oedema, pruritus, erythema, paraesthesia, loss of consciousness, vomiting, urticaria, flushing, dyspnoea, nausea, incontinence of urine and stool, cold sweats, shivering, chills, increased blood pressure, lip swelling, burning sensation, drug eruption, arthralgia, leg swelling, and tachycardia.
Investigations
Marked and persistent increases of serum transaminases have been reported infrequently (see section 4.4). In controlled clinical studies, the incidence of clinically important elevations in serum transaminases (ALT and/or AST > 3 X ULN, consecutive) was 1.0 % for patients treated with Pelzont with or without a statin. These elevations were generally asymptomatic and returned to baseline after discontinuation of therapy or with continued treatment.
Clinically important elevations of CK (> 10 X ULN) were seen in 0.3 % of the patients treated with Pelzont with or without a statin (see section 4.4).
Other abnormal laboratory values reported were elevations in LDH, fasting glucose, uric acid, total bilirubin, and amylase, and reductions in phosphorus and platelet counts (see section 4.4).
As with other nicotinic acid medicinal products, elevations in fasting glucose (a median increase of approximately 4 mg/dL), and uric acid (mean change from baseline of +14.7 %), and reductions in platelet counts (a mean change from baseline of –14.0 %) were reported in controlled clinical studies with Pelzont (2,000 mg/40 mg) (see section 4.4). In diabetic patients a median increase in HbA1c of 0.2 % was observed (where modification of hypoglycaemic therapy was allowed).
Additional adverse reactions reported with other nicotinic acid medical products
Additional adverse reactions that have been reported with other nicotinic acid medicinal products (with or without a statin) in post-marketing use or in clinical trials include the following:
Eye disorders: Cystoid macular oedema, toxic amblyopia.
4.9 Overdose
Pelzont
In the event of an overdose, it is reasonable to employ the usual symptomatic and supportive measures. Cases of overdose have been reported; the maximum dose of Pelzont taken was 5,000 mg/100 mg. All patients recovered without sequelae. The most commonly reported adverse reactions from the subjects who received this higher dose were consistent with a high dose of nicotinic acid and included: flushing, headache, pruritus, nausea, dizziness, vomiting, diarrhoea, epigastric and abdominal pain/discomfort, and back pain. Laboratory abnormalities included increased amylase and lipase, decreased haematocrit and occult blood in the stool.
Nicotinic acid
For an overdose of nicotinic acid, supportive measures should be employed.
Laropiprant
During controlled clinical trials in healthy subjects, single doses of up to 900 mg laropiprant and multiple doses up to 450 mg once daily for 10 days were generally well tolerated. There is no experience with doses of laropiprant above 900 mg in humans. Prolongation of collagen-induced platelet aggregation was observed in subjects taking multiple doses of 300 mg or greater (see section 5.1).
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
5.3 Preclinical safety data
Pelzont
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to human use.
The safety of concomitant administration of nicotinic acid and laropiprant was assessed in dogs and rats. Toxicologic findings in these co-administration studies were consistent with those seen with nicotinic acid and laropiprant administered individually.
Nicotinic acid
Degeneration in the stomach and hepatocyte vacuolation were observed in rats following 6 months of dosing at systemic exposure values at least 179 times the human exposure based on the AUC of the recommended daily human dose. Retinopathy and/or corneal lesions were observed in dogs following 6 months of dosing at systemic exposure values at least 240 times the human exposure based on the AUC of the recommended daily human dose.
Nicotinic acid was not carcinogenic in mice when administered for the duration of their life. Mice in this study received approximately 9 to 13 times a human nicotinic acid dose of 2,000 mg/day as determined on a mg/m2 basis. Nicotinic acid showed no mutagenic effects in the in vitro assays.
No nicotinic acid-related adverse effects on fertility were observed in male and female rats up to exposure levels approximately 391 times the human AUC of nicotinic acid based on the AUC of the recommended daily human dose.
Nicotinic acid was not teratogenic in rats and rabbits up to exposure levels approximately 253 and 104 times the human AUC of nicotinic acid at the recommended daily human dose, respectively. In rats, foetotoxic effects (significantly decreased foetal body weights associated with a decrease in the number of ossified sacrocaudal vertebrae and an increased incidence of foetuses with sites of incomplete ossification) were noted in the absence of any signs of maternal toxicity at exposure levels approximately 959 times the human AUC of nicotinic acid at the recommended daily human dose. Similar treatment-related changes were observed in rabbit foetuses but in the presence of maternal toxicity at exposure levels approximately 629 times the human AUC of nicotinic acid at the recommended daily human dose.
Laropiprant
Ketonuria and hepatocellular centrilobular hypertrophy were observed in rats in repeated dose toxicity studies for up to 6 months dosing. The hepatocellular centrilobular hypertrophy was consistent with rodent specific enzyme induction. The no-observed-adverse-effect level (NOAEL) was at least 118 times the human exposure based on the AUC of the recommended daily human dose.
Increases in serum alanine aminotransferase (ALT) levels were observed in all dog studies, at systemic exposure levels at least 14 times the human exposure based on the AUC of the recommended daily human dose. No other effects were observed in dog studies with exposures at least 100 times the human exposure based on the AUC of the recommended daily human dose.
Laropiprant was not carcinogenic in 2 year studies in mice and rats at the highest doses tested, which represents at least 218 to 289 times the human exposure based on the AUC of the recommended daily human dose.
Laropiprant was not mutagenic or clastogenic in a series of genetic toxicology studies.
No adverse effects on fertility were observed in male or female rats given laropiprant prior to mating and throughout mating, at systemic exposure levels at least 289 times the human exposure based on the AUC of the recommended daily human dose.
Laropiprant was not teratogenic in rats or in rabbits at systemic exposure levels at least 153 and 438 times the human exposure based on the AUC of the recommended daily human dose. Reproduction toxicity studies showed slight treatment-related decreases in mean maternal weight gain and foetal body weight, slight increases in pup mortality, and increased incidence of supernumerary rib and incomplete ossification of the sternebra in the foetus were observed in rats at systemic exposure levels at least 513 times the human exposure based on the AUC of the recommended daily human dose.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Hypromellose (E464)
Colloidal anhydrous silica (E551)
Sodium stearyl fumarate
Hydroxypropylcellulose (E463)
Microcrystalline cellulose (E460) Croscarmellose sodium
Lactose monohydrate Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
PVC/Aclar blisters: 2 years.
Aluminium/Aluminium blisters: 18 months.
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Opaque PVC/Aclar blister with push-through aluminium lidding containing 14 modified-release , 28, 56, 84, 98, 168, 196 modified-release tablets, multi-packs containing 196 ified-release tablets and 49 × 1 modified-release tablets in a perforated unit dose
tablets. Pack siz (2 packs of 98 blister.
Aluminium/Aluminium blister with push-through lidding containing 7 modified-release tablets. Pack sizes of 14, 28, 56, 168 modified-release tablets and 32 × 1 modified-release tablets in a perforated unit dose blister.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd. Hertford Road, Hoddesdon Hertfordshire EN11 9BU United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/08/460/001
EU/1/08/460/002
EU/1/08/460/003
EU/1/08/460/004
EU/1/08/460/005
EU/1/08/460/006
EU/1/08/460/007
EU/1/08/460/008
EU/1/08/460/009
EU/1/08/460/010
EU/1/08/460/011
EU/1/08/460/012
EU/1/08/460/013
EU/1/08/460/014
9. DATE OF FIRST AUTHORISATION/REN
9. DATE OF FIRST AUTHORISATION/RENDate of first authorisation: 3 July 2008