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Rasagiline Milpharm 1 mg tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazard for humans based on standard studies of safety pharmacology, repeated dose toxicity, genotoxicity, reproduction and development.
Rasagiline did not present genotoxic potential in vivo and in several in vitro systems using bacteria or hepatocytes. In the presence of metabolite activation rasagiline induced an increase of chromosomal aberrations at concentrations with excessive cytotoxicity which are unattainable at the clinical conditions of use.
Rasagiline was not carcinogenic in rats at systemic exposure, 84 – 339 times the expected plasma exposures in humans at 1 mg/day. In mice, increased incidences of combined bronchiolar/alveolar adenoma and/or carcinoma were observed at systemic exposures, 144 - 213 times the expected plasma exposure in humans at 1 mg/day.
6. |
Rasagiline Milpharm 1 mg tablets | Pharmaceutical particulars - List of excipients | List of excipients
Cellulose, microcrystalline
Tartaric acid
Maize starch
Starch, pregelatinized maize
Talc
Stearic acid
6.2 |
Rasagiline Milpharm 1 mg tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Rasagiline Milpharm 1 mg tablets | Pharmaceutical particulars - Shelf life | Shelf life
30 months.
6.4 |
Rasagiline Milpharm 1 mg tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C.
6.5 |
Rasagiline Milpharm 1 mg tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
OPA/Al/PVC/Al blister packs of 7, 10, 28, 30, 50, 90, 100 and 112 tablets.
PVC/PVDC/Al blister packs of 7, 10, 28, 30, 50, 90, 100 and 112 tablets.
Not all pack sizes may be marketed.
6.6 |
Rasagiline Milpharm 1 mg tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements for disposal.
7. |
Rasagiline Milpharm 1 mg tablets | Marketing authorisation holder | Milpharm Limited
Ares Block, Odyssey Business Park
West End Road
Ruislip HA4 6QD
United Kingdom
8. Marketing authorisation number(s)
PL 16363/0501
9. |
Rasagiline Milpharm 1 mg tablets | Date of first authorisation/renewal of the authorisation | 12/11/2015
10. |
Rasagiline Milpharm 1 mg tablets | Date of revision of the text | 29/03/2021 |
Rasagiline Rivopharm 1 mg tablet | Name of the medicinal product | Rasagiline Rivopharm 1 mg tablets
2. |
Rasagiline Rivopharm 1 mg tablet | Qualitative and quantitative composition | Each tablet contains 1 mg rasagiline (equivalent to 1.438 mg rasagiline hemitartrate).
For the full list of excipients, see section 6.1.
3. |
Rasagiline Rivopharm 1 mg tablet | Pharmaceutical form | Tablets
White to off white round, flat tablets with bevelled edges and engraved with “1” in one side, with a diameter of 8 mm.
4. |
Rasagiline Rivopharm 1 mg tablet | Clinical particulars - Therapeutic indications | Therapeutic indications
Rasagiline Rivopharm 1 mg tablets is indicated for the treatment of idiopathic Parkinson's disease (PD) as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations.
4.2 |
Rasagiline Rivopharm 1 mg tablet | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Rasagiline Rivopharm 1 mg tablets is administered orally, at a dose of 1 mg once daily with or without levodopa.
Elderly
No change in dose is required for elderly patients.
Paediatric population
Rasagiline is not recommended for use in children and adolescents due to lack of data on safety and efficacy.
Patients with hepatic impairment
Rasagiline Rivopharm 1 mg tablets use in patients with severe hepatic impairment is contraindicated (see section 4.3). Rasagiline Rivopharm 1 mg tablets use in patients with moderate hepatic impairment should be avoided. Caution should be used when initiating treatment with Rasagiline Rivopharm 1 mg tablets in patients with mild hepatic impairment. In case patients progress from mild to moderate hepatic impairment Rasagiline Rivopharm 1 mg tablets should be stopped (see section 4.4).
Patients with renal impairment
No change in dose is required for renal impairment.
Method of administration
Rasagiline Rivopharm 1 mg tablets is administered orally.
It may be taken with or without food.
4.3 |
Rasagiline Rivopharm 1 mg tablet | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concomitant treatment with other monoamine oxidase (MAO) inhibitors (including medicinal and natural products without prescription e.g. St. John's Wort) or pethidine (see section 4.5). At least 14 days must elapse between discontinuation of Rasagiline Rivopharm 1 mg tablets and initiation of treatment with MAO inhibitors or pethidine.
Rasagiline Rivopharm 1 mg tablets is contraindicated in patients with severe hepatic impairment.
4.4 |
Rasagiline Rivopharm 1 mg tablet | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Concomitant use of rasagiline with other medicinal products
The concomitant use of Rasagiline Rivopharm 1 mg tablets and fluoxetine or fluvoxamine should be avoided (see section 4.5). At least five weeks should elapse between discontinuation of fluoxetine and initiation of treatment with Rasagiline Rivopharm 1 mg tablets. At least 14 days should elapse between discontinuation of Rasagiline Rivopharm 1 mg tablets and initiation of treatment with fluoxetine or fluvoxamine. The concomitant use of rasagiline and dextromethorphan or sympathomimetics such as those present in nasal and oral decongestants or cold medicinal product containing ephedrine or pseudoephedrine is not recommended (see section 4.5).
Concomitant use of rasagiline and levodopa
Since rasagiline potentiates the effects of levodopa, the adverse effects of levodopa may be increased and pre-existing dyskinesia exacerbated. Decreasing the dose of levodopa may ameliorate this side effect. There have been reports of hypotensive effects when rasagiline is taken concomitantly with levodopa. Patients with Parkinson's disease are particularly vulnerable to the adverse effects of hypotension due to existing gait issues.
Dopaminergic effects
Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes
Rasagiline may cause daytime drowsiness, somnolence, and, occasionally, especially if used with other dopaminergic medicinal products - falling asleep during activities of daily living. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with rasagiline. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines (see section 4.7).
Impulse control disorders (ICDs)
Impulse control disorders (ICDs) can occur in patients treated with dopamine agonists and/or dopaminergic treatments. Similar reports of ICDs have also been received post-marketing with rasagiline. Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware of the behavioral symptoms of impulse control disorders that were observed in patients treated with rasagiline, including cases of compulsions, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behaviour and compulsive spending or buying.
Melanoma
A retrospective cohort study suggested a possibly increased risk of melanoma with the use of rasagiline, especially in patients with longer duration of rasagiline exposure and/or with the higher cumulative dose of rasagiline. Any suspicious skin lesion should be evaluated by a specialist. Patients should therefore be advised to seek medical review if a new or changing skin lesion is identified.
Hepatic impairment
Caution should be used when initiating treatment with Rasagiline Rivopharm 1 mg tablets in patients with mild hepatic impairment. Rasagiline Rivopharm 1 mg tablets use in patients with moderate hepatic impairment should be avoided. In case patients progress from mild to moderate hepatic impairment, Rasagiline Rivopharm 1 mg tablets should be stopped (see section 5.2).
4.5 |
Rasagiline Rivopharm 1 mg tablet | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
There are a number of known interactions between non selective MAO inhibitors and other medicinal products.
Rasagiline Rivopharm 1 mg tablets must not be administered along with other MAO inhibitors (including medicinal and natural products without prescription e.g. St. John's Wort) as there may be a risk of non-selective MAO inhibition that may lead to hypertensive crises (see section 4.3).
Serious adverse reactions have been reported with the concomitant use of pethidine and MAO inhibitors including another selective MAO-B inhibitor. The concomitant administration of Rasagiline Rivopharm 1 mg tablets and pethidine is contraindicated (see section 4.3).
With MAO inhibitors there have been reports of medicinal product interactions with the concomitant use of sympathomimetic medicinal products. Therefore, in view of the MAO inhibitory activity of rasagiline, concomitant administration of Rasagiline Rivopharm 1 mg tablets and sympathomimetics such as those present in nasal and oral decongestants or cold medicinal products, containing ephedrine or pseudoephedrine, is not recommended (see section 4.4).
There have been reports of medicinal product interactions with the concomitant use of dextromethorphan and non-selective MAO inhibitors. Therefore, in view of the MAO inhibitory activity of rasagiline, the concomitant administration of Rasagiline Rivopharm 1 mg tablets and dextromethorphan is not recommended (see section 4.4).
The concomitant use of Rasagiline Rivopharm 1 mg tablets and fluoxetine or fluvoxamine should be avoided (see section 4.4).
For concomitant use of Rasagiline Rivopharm 1 mg tablets with selective serotonin reuptake inhibitors (SSRIs)/selective serotonin-norepinephrine reuptake inhibitors (SNRIs) in clinical trials, see section 4.8.
Serious adverse reactions have been reported with the concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants and MAO inhibitors. Therefore, in view of the MAO inhibitory activity of rasagiline, antidepressants should be administered with caution.
In Parkinson's disease patients receiving chronic levodopa treatment as adjunct therapy, there was no clinically significant effect of levodopa treatment on rasagiline clearance.
In vitro metabolism studies have indicated that cytochrome P450 1A2 (CYP1A2) is the major enzyme responsible for the metabolism of rasagiline. Co-administration of rasagiline and ciprofloxacin (an inhibitor of CYP1A2) increased the AUC of rasagiline by 83%. Co-administration of rasagiline and theophylline (a substrate of CYP1A2) did not affect the pharmacokinetics of either product. Thus, potent CYP1A2 inhibitors may alter rasagiline plasma levels and should be administered with caution.
There is a risk that the plasma levels of rasagiline in smoking patients could be decreased, due to induction of the metabolising enzyme CYP1A2.
In vitro studies showed that rasagiline at a concentration of 1 μg/ml (equivalent to a level that is 160 times the average Cmax ~ 5.9-8.5 ng/ml in Parkinson's disease patients after 1 mg rasagiline multiple dosing), did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A. These results indicate that rasagiline's therapeutic concentrations are unlikely to cause any clinically significant interference with substrates of these enzymes.
Concomitant administration of rasagiline and entacapone increased rasagiline oral clearance by 28%.
Tyramine/rasagiline interaction: Results of five tyramine challenge studies (in volunteers and PD patients), together with results of home monitoring of blood pressure after meals (of 464 patients treated with 0.5 or 1 mg/day of rasagiline or placebo as adjunct therapy to levodopa for six months without tyramine restrictions), and the fact that there were no reports of tyramine/rasagiline interaction in clinical studies conducted without tyramine restriction, indicate that Rasagiline Rivopharm 1 mg tablets can be used safely without dietary tyramine restrictions.
4.6 |
Rasagiline Rivopharm 1 mg tablet | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of rasagiline in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of rasagiline during pregnancy.
Breast-feeding
Non-clinical data indicate that rasagiline inhibits prolactin secretion and thus, may inhibit lactation.
It is not known whether rasagiline is excreted in human milk. Caution should be exercised when rasagiline is administered to a breast-feeding mother.
Fertility
No human data on the effect of rasagiline on fertility are available. Non-clinical data indicate that rasagiline has no effect on fertility.
4.7 |
Rasagiline Rivopharm 1 mg tablet | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
In patients experiencing somnolence/sudden sleep episodes, rasagiline may have major influence on the ability to drive and use machines.
Patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that rasagiline does not affect them adversely.
Patients being treated with rasagiline and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until they have gained sufficient experience with rasagiline and other dopaminergic medications to gauge whether or not it affects their mental and/or motor performance adversely.
If increased somnolence or new episodes of falling asleep during activities of daily living (e.g. watching television, passenger in a car, etc.) are experienced at any time during treatment, the patients should not drive or participate in potentially dangerous activities.
Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of rasagiline.
Patients should be cautioned about possible additive effects of sedating medicinal products, alcohol, or other central nervous system depressants (e.g. benzodiazepines, antipsychotics, antidepressants) in combination with rasagiline, or when taking concomitant medications that increase plasma levels of rasagiline (e.g. ciprofloxacin) (see section 4.4).
4.8 |
Rasagiline Rivopharm 1 mg tablet | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
In clinical studies in Parkinson's disease patients the most commonly reported adverse reactions were: headache, depression, vertigo, and flu (influenza and rhinitis) in monotherapy; dyskinesia, orthostatic hypotension, fall, abdominal pain, nausea and vomiting, and dry mouth in adjunct to levodopa therapy; musculoskeletal pain, as back and neck pain, and arthralgia in both regimens. These adverse reactions were not associated with an elevated rate of drug discontinuation.
Tabulated list of adverse reactions
Adverse reactions are ranked under headings of frequency using the following conventions: 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) or not known (cannot be estimated from the available data).
Monotherapy
The list below includes adverse reactions which were reported with a higher incidence in placebo controlled studies, in patients receiving 1 mg/day rasagiline.
System organ class
Very common
Common
Uncommon
Not known
Infections and infestations
Influenza
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Skin carcinoma
Blood and lymphatic system disorders
Leucopenia
Immune system disorders
Allergy
Metabolism and nutrition disorders
Decreased appetite
Psychiatric disorders
Depression, Hallucinations*
Impulse control disorders*
Nervous system disorders
Headache
Cerebrovascular accident
Serotonin syndrome*, Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes*
Eye disorders
Conjunctivitis
Ear and labyrinth disorders
Vertigo
Cardiac disorders
Angina pectoris
Myocardial infarction
Vascular disorders
Hypertension*
Respiratory, thoracic and mediastinal disorders
Rhinitis
Gastrointestinal disorders
Flatulence
Skin and subcutaneous tissue disorders
Dermatitis
Vesiculobullous rash
Musculoskeletal and connective tissue disorders
Musculoskeletal pain, Neck pain, Arthritis
Renal and urinary disorders
Urinary urgency
General disorders and administration site conditions
Fever, Malaise
*See section description of selected adverse reactions
4 Adjunct Therapy
5 The list below includes adverse reactions which were reported with a higher incidence in placebo controlled studies in patients receiving 1 mg/day rasagiline
System organ class
Very common
Common
Uncommon
Not known
Neoplasms benign, malignant and unspecified
Skin melanoma*
Metabolism and nutrition disorders
Decreased appetite
Psychiatric disorders
Hallucinations*, Abnormal dreams
Confusion
Impulse control disorders*
Nervous system disorders
Dyskinesia
Dystonia, Carpal tunnel syndrome, Balance disorder
Cerebrovascular accident
Serotonin syndrome*, Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes*
Cardiac disorders
Angina pectoris
Vascular disorders
Orthostatic hypotension*
Hypertension*
Gastrointestinal disorders
Abdominal pain , Constipation, Nausea and vomiting, Dry mouth
Skin and subcutaneous tissue disorders
Rash
Musculoskeletal and connective tissue disorders*
Arthralgia, Neck pain
Investigations
Decreased weight
Injury, poisoning and procedural complications
Fall
*See section description of selected adverse reactions
Description of selected adverse reactions
Orthostatic hypotension
In blinded placebo-controlled studies, severe orthostatic hypotension was reported in one subject (0.3%) in the rasagiline arm (adjunct studies), none in the placebo arm. Clinical trial data further suggest that orthostatic hypotension occurs most frequently in the first two months of rasagiline treatment and tends to decrease over time.
Hypertension
Rasagiline selectively inhibits MAO-B and is not associated with increased tyramine sensitivity at the indicated dose (1 mg/day). In blinded placebo-controlled studies (monotherapy and adjunct) severe hypertension was not reported in any subjects in the rasagiline arm. In the post-marketing period, cases of elevated blood pressure, including rare serious cases of hypertensive crisis associated with ingestion of unknown amounts of tyramine-rich foods, have been reported in patients taking rasagiline. In post-marketing period, there was one case of elevated blood pressure in a patient using the ophthalmic vasoconstrictor tetrahydrozoline hydrochloride while taking rasagiline.
Impulse control disorders
One case of hypersexuality was reported in monotherapy placebo-controlled study. The following were reported during post-marketing exposure with unknown frequency: compulsions, compulsive shopping, dermatillomania, dopamine dysregulation syndrome, impulse-control disorder, impulsive behaviour, kleptomania, theft, obsessive thoughts, obsessive-compulsive disorder, stereotypy, gambling, pathological gambling, libido increased, hypersexuality, psychosexual disorder, sexually inappropriate behaviour. Half of the reported ICD cases were assessed as serious. Only single cases of reported cases had not recovered at the time they were reported.
Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes
Excessive daily sleepiness (hypersomnia, lethargy, sedation, sleep attacks, somnolence, sudden onset of sleep) can occur in patients treated with dopamine agonists and/or other dopaminergic treatments. A similar pattern of excessive daily sleepiness has been reported post-marketing with rasagiline.
Cases of patients, treated with rasagiline and other dopaminergic medicinal products, falling asleep while engaged in activities of daily living have been reported. Although many of these patients reported somnolence while on rasagiline with other dopaminergic medicinal products, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported more than 1-year after initiation of treatment.
Hallucinations
Parkinson's disease is associated with symptoms of hallucinations and confusion. In post marketing experience, these symptoms have also been observed in Parkinson's disease patients treated with rasagiline.
Serotonin syndrome
Rasagiline clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with rasagiline, but the following antidepressants and doses were allowed in the rasagiline trials: amitriptyline ≤ 50 mg/daily, trazodone ≤ 100 mg/daily, citalopram ≤ 20 mg/daily, sertraline ≤ 100 mg/daily, and paroxetine ≤ 30 mg/daily (see section 4.5). In the post-marketing period, cases of potentially life-threating serotonin syndrome associated with agitation, confusion, rigidity, pyrexia and myoclonus have been reported by patients treated with antidepressants, meperidine, tramadol, methadone, or propoxyphene concomitantly with rasagiline.
Malignant melanoma
Incidence of skin melanoma in placebo-controlled clinical studies was 2/380 (0.5%) in rasagiline 1 mg as adjacent to levodopa therapy group vs. 1/388 (0.3%) incidence in placebo group. Additional cases of malignant melanoma were reported during post-marketing period. These cases were considered serious in all reports.
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 |
Rasagiline Rivopharm 1 mg tablet | Clinical particulars - Overdose | Overdose
Overdosage: Symptoms reported following overdose of rasagiline in doses ranging from 3 mg to 100 mg included dysphoria, hypomania, hypertensive crisis and serotonin syndrome. |
Rasagiline Rivopharm 1 mg tablet | Clinical particulars - Subsection 10 | Overdose can be associated with significant inhibition of both MAO-A and MAO-B. In a single-dose study healthy volunteers received 20 mg/day and in a ten-day study healthy volunteers received 10 mg/day. Adverse events were mild or moderate and not related to rasagiline treatment. In a dose escalation study in patients on chronic levodopa therapy treated with 10 mg/day of rasagiline, there were reports of cardiovascular undesirable reactions (including hypertension and postural hypotension) which resolved following treatment discontinuation. These symptoms may resemble those observed with nonselective MAO inhibitors.
There is no specific antidote. In case of overdose, patients should be monitored and the appropriate symptomatic and supportive therapy instituted.
5. Pharmacological properties
5.1 |
Rasagiline Rivopharm 1 mg tablet | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 0.5 hours. The absolute bioavailability of a single rasagiline dose is about 36%.
Food does not affect the Tmax of rasagiline, although Cmax and exposure (AUC) are decreased by approximately 60% and 20%, respectively, when the medicinal product is taken with a high fat meal.
Because AUC is not substantially affected, rasagiline can be administered with or without food.
Distribution
The mean volume of distribution following a single intravenous dose of rasagiline is 243 l.
Plasma protein binding following a single oral dose of 14C-labelled rasagiline is approximately 60 to 70%.
Biotransformation
Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through two main pathways: N-dealkylation and/or hydroxylation to yield: 1-Aminoindan, 3-hydroxy-N-propargyl-1 aminoindan and 3-hydroxy-1-aminoindan. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on cytochrome P450 system, with CYP1A2 being the major iso-enzyme involved in rasagiline metabolism. Conjugation of rasagiline and its metabolites was also found to be a major elimination pathway to yield glucuronides.
Elimination
After oral administration of 14C-labelled rasagiline, elimination occurred primarily via urine (62.6%) and secondarily via faeces (21.8%), with a total recovery of 84.4% of the dose over a period of 38 days. Less than 1% of rasagiline is excreted as unchanged product in urine.
Linearity/non-linearity
Rasagiline pharmacokinetics are linear with dose over the range of 0.5-2 mg. Its terminal half-life is 0.6-2 hours.
Characteristics in patients
Patients with hepatic impairment
In subjects with mild hepatic impairment, AUC and Cmax were increased by 80% and 38%, respectively. In subjects with moderate hepatic impairment, AUC and Cmax were increased by 568% and 83%, respectively (see section 4.4).
Patients with renal impairment
Rasagiline's pharmacokinetics characteristics in subjects with mild (CLcr 50-80 ml/min) and moderate (CLcr 30-49 ml/min) renal impairment were similar to healthy subjects.
5.3 |
Rasagiline Rivopharm 1 mg tablet | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and reproduction toxicity.
Rasagiline did not present genotoxic potential in vivo and in several in vitro systems using bacteria or hepatocytes. In the presence of metabolite activation rasagiline induced an increase of chromosomal aberrations at concentrations with excessive cytotoxicity which are unattainable at the clinical conditions of use.
Rasagiline was not carcinogenic in rats at systemic exposure, 84 – 339 times the expected plasma exposures in humans at 1 mg/day. In mice, increased incidences of combined bronchiolar/alveolar adenoma and/or carcinoma were observed at systemic exposures, 144 - 213 times the expected plasma exposure in humans at 1 mg/day.
6. |
Rasagiline Rivopharm 1 mg tablet | Pharmaceutical particulars - List of excipients | List of excipients
Cellulose, Microcrystalline
(Maize) starch, (partially) pregelatinised
Silica, Colloidal Anhydrous
Magnesium Stearate
6.2 |
Rasagiline Rivopharm 1 mg tablet | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable
6.3 |
Rasagiline Rivopharm 1 mg tablet | Pharmaceutical particulars - Shelf life | Shelf life
3 years
6.4 |
Rasagiline Rivopharm 1 mg tablet | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special temperature storage conditions. Store in the original immediate package to protect from light.
6.5 |
Rasagiline Rivopharm 1 mg tablet | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Aluminium/aluminium blister packs of 28 tablets.
6.6 |
Rasagiline Rivopharm 1 mg tablet | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements.
7. |
Rasagiline Rivopharm 1 mg tablet | Marketing authorisation holder | Rivopharm UK Ltd.
30th Floor, 40 Bank Street
Canary Wharf
London
E14 5NR
United Kingdom
8. Marketing authorisation number(s)
PL 33155/0041
9. |
Rasagiline Rivopharm 1 mg tablet | Date of first authorisation/renewal of the authorisation | 09/09/2016
10. |
Rasagiline Rivopharm 1 mg tablet | Date of revision of the text | 10/06/2021 |
Ravicti 1.1 g/ml oral liquid | Name of the medicinal product | RAVICTI 1.1 g/ml oral liquid
2. |
Ravicti 1.1 g/ml oral liquid | Qualitative and quantitative composition | Each ml of liquid contains 1.1 g of glycerol phenylbutyrate. This corresponds to a density of 1.1 g/ml.
3. |
Ravicti 1.1 g/ml oral liquid | Pharmaceutical form | Oral liquid.
Clear, colourless to pale yellow liquid.
4. |
Ravicti 1.1 g/ml oral liquid | Clinical particulars - Therapeutic indications | Therapeutic indications
RAVICTI is indicated for use as adjunctive therapy for chronic management of patients with urea cycle disorders (UCDs) including deficiencies of carbamoyl phosphate synthetase I (CPS), ornithine carbamoyltransferase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginase I (ARG) and ornithine translocase deficiency hyperornithinaemia-hyperammonaemia homocitrullinuria syndrome (HHH) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone.
RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).
4.2 |
Ravicti 1.1 g/ml oral liquid | Clinical particulars - Posology and method of administration | Posology and method of administration
RAVICTI should be prescribed by a physician experienced in the management of UCDs.
Posology
RAVICTI must be used with dietary protein restriction and sometimes dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements) depending on the daily dietary protein intake needed to promote growth and development.
The daily dose should be individually adjusted according to the patient's protein tolerance and the daily dietary protein intake needed.
RAVICTI therapy may be required life long unless orthotopic liver transplantation is elected.
Adults and children
The recommended dose for patients naïve to phenylbutyric acid and for patients switching from sodium phenylbutyrate or from sodium phenylacetate/sodium benzoate injection to RAVICTI are different.
The recommended total daily dose of RAVICTI is based on body surface area and ranges from 4.5 ml/m2/day to 11.2 ml/m2/day (5.3 g/m2/day to 12.4 g/m2/day) and should take into account the following:
The total daily dose should be divided into equal amounts and given with each meal or feeding (e.g. three times to six times per day). Each dose should be rounded up to the nearest 0.1 ml for patients less than 2 years of age and 0.5 ml for patients 2 years of age and older.
Recommended starting dose in phenylbutyrate-naïve patients
• 8.5 ml/m2/day (9.4 g/m2/day) in patients with a body surface area (BSA) < 1.3 m2
• 7 ml/m2/day (8 g/m2/day) in patients with a BSA ≥ 1.3 m2
Initial dose in patients switching from sodium phenylbutyrate to RAVICTI
Patients switching from sodium phenylbutyrate to RAVICTI should receive the dose of RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows:
• Total daily dose of RAVICTI (ml) = total daily dose of sodium phenylbutyrate tablets (g) x 0.86
• Total daily dose of RAVICTI (ml) = total daily dose of sodium phenylbutyrate powder (g) x 0.81
Initial dose in patients switching from sodium phenylacetate/sodium benzoate injection to RAVICTI
Once stable with controlled ammonia, patients switching from sodium phenylacetate/sodium benzoate to RAVICTI should receive a dose of RAVICTI at the higher end of the treatment range (11.2 ml/m2/day) with measurements of plasma ammonia to guide further dosing.
The recommended daily dose schedule of 8.5 ml/m2/day - 11.2 ml/m2/day over a period of up to 24 hours for patients stabilised with no further hyperammonaemia is as follows:
• Step 1: 100% dose sodium phenylacetate/sodium benzoate and 50% dose of RAVICTI for 4-8 hours;
• Step 2: 50% dose sodium phenylacetate/sodium benzoate and 100% RAVICTI for 4-8 hours;
• Step 3: sodium phenylacetate/sodium benzoate discontinued and full dose RAVICTI continued according to feeding schedule for 4-8 hours.
For data regarding pharmacodynamic and pharmacokinetic properties in this age group, see sections 5.1 and 5.2.
Dose adjustment and monitoring in adults and children
The daily dose should be individually adjusted according to the patient's estimated urea synthetic capacity, if any, protein tolerance and the daily dietary protein intake needed to promote growth and development. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered 4-phenylbutyric acid (PBA) dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated glycerol phenylbutyrate dose for a 24-hour period is 0.6 ml glycerol phenylbutyrate per gram of dietary protein ingested per 24 hour period assuming all the waste nitrogen is covered by glycerol phenylbutyrate and excreted as phenylacetylglutamine (PAGN).
Adjustment based on plasma ammonia
The dose of glycerol phenylbutyrate should be adjusted to produce a fasting plasma ammonia level that is less than half the upper limit of normal (ULN) in patients 6 years and older. In infants and young children (generally below 6 years of age) where obtaining fasting ammonia is problematic due to frequent feedings, the first ammonia of the morning should be kept below the ULN.
Adjustment based on urinary phenylacetylglutamine
U-PAGN measurements may be used to help guide glycerol phenylbutyrate dose adjustment and assess compliance. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the recommended ULN, the glycerol phenylbutyrate dose should be adjusted upward. The amount of dose adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-h U-PAGN level and the estimated glycerol phenylbutyrate dose needed per gram of dietary protein ingested.Spot U-PAGN concentrations below the following levels may indicate improper medicinal product administration and/or lack of compliance:
• 9,000 microgram (mcg)/ml for patients under 2 years of age
• 7,000 microgram (mcg)/ml for patients ≥2 years of age with a BSA of ≤1.3
• 5,000 microgram (mcg)/ml for patients ≥2 years of age with a BSA of >1.3
If spot U-PAGN concentrations fall below these levels, assess compliance with medicinal product and/or effectiveness of medicinal product administration (e.g., via feeding tube) and consider increasing the glycerol phenylbutyrate dose in compliant patients to achieve optimal ammonia control (within normal limit for patients under 2 years of age and less than half ULN in older patients when fasted).
Adjustment based on plasma phenylacetate and phenylacetylglutamine
Symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness in the absence of high ammonia or intercurrent illness may be signs of phenylacetic acid (PAA) toxicity (see section 4.4, PAA toxicity). Therefore, measurement of plasma PAA and PAGN levels may be useful to guide dosing. The plasma PAA to PAGN (both measured in mcg/ml) ratio has been observed to be generally less than 1 in patients without PAA accumulation. In patients with a PAA to PAGN ratio exceeding 2.5, a further increase in glycerol phenylbutyrate dose may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction. In such cases, increasing the dosing frequency may result in a lower plasma PAA level and PAA to PAGN ratio. Ammonia levels must be monitored closely when changing the dose of glycerol phenylbutyrate.
N-acetylglutamate synthase (NAGS) and CITRIN (citrullinaemia type 2)
deficiency
The safety and efficacy of RAVICTI for the treatment of patients with N-acetylglutamate synthase (NAGS) and CITRIN (citrullinaemia type 2) deficiency have not been established.
Paediatric population
Posology is the same for adult and paediatric patients.
Missed dose
Any missed dose should be taken as soon as recognised. However, if the next scheduled dose is within 2 hours for adults and within 30 minutes for children, the missed dose should be omitted and the usual dosing schedule resumed. The dose should not be doubled to make up for a missed dose.
Special populations
Elderly (65 years or older)
Clinical studies of RAVICTI did not include sufficient numbers of subjects ≥ 65 years of age to determine whether they respond differently than younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other medicinal product therapy.
Hepatic impairment
Because conversion of PAA to PAGN occurs in the liver, patients with severe hepatic impairment may have reduced conversion capability and higher plasma PAA and plasma PAA to PAGN ratio. Therefore, dose for adult and paediatric patients with mild, moderate or severe hepatic impairment should be started at the lower end of the recommended dosing range (4.5 ml/m2/day) and kept at the lowest dose necessary to control the patient's ammonia levels. A plasma PAA to PAGN ratio exceeding 2.5 may indicate saturation of PAA to PAGN conversion capacity and the need for reduced dosing and/or increased frequency of dosing. The plasma PAA to PAGN ratio may be useful in dose monitoring (see section 5.2).
Renal impairment
No studies were conducted in UCD patients with renal impairment; the safety of glycerol phenylbutyrate in patients with renal impairment is unknown. RAVICTI should be used with caution in patients with severe renal impairment. Preferably such patients should be started and maintained at the lowest dose necessary to control the blood ammonia levels.
Method of administration
Oral or gastroenteral use.
RAVICTI should be taken with meals and administered directly into the mouth via an oral syringe. The medicinal product should not be added or stirred into a large volume of other liquid, as glycerol phenylbutyrate is heavier than water and this may result in incomplete administration. Compatibility studies have been conducted (see section 4.5). RAVICTI may be added to a small amount of apple sauce, ketchup, or squash puree and should be used within 2 hours when stored at room temperature (25 °C). The medicinal product may be mixed with medical formulas (Cyclinex-1, Cyclinex-2, UCD-1, UCD-2, Polycose, Pro Phree and Citrulline) and used within 2 hours when stored at 25 °C, or up to 24 hours, refrigerated.
Patients should be advised that CE marked oral syringes compatible with the integrated syringe insert in the bottle, with suitable size for the prescribed dosing volume can be obtained from a pharmacy (see section 6.6).
The RAVICTI bottle should be opened by pushing down on the cap and twisting to the left. The tip of the oral syringe should be placed into the syringe insert and the bottle should be turned upside down with the syringe still inserted. The oral syringe should then be filled by pulling the plunger back until the syringe is filled with the prescribed amount of medicinal product. The oral syringe should be tapped to remove air bubbles, while making sure it is filled with the correct amount of liquid. The liquid can be swallowed from the oral syringe or the oral syringe can be attached to a gastrostomy or nasogastric tube. The same oral syringe should be used for all doses taken each day. It is important to ensure that the oral syringe is kept clean and dry between the dosing intervals. The oral syringe should not be rinsed between daily doses, as the presence of water causes glycerol phenylbutyrate to degrade. The bottle should be closed tightly after use. The oral syringe should be discarded after the last dose of the day.
RAVICTI may also be administered by CE marked medical grade silicone nasogastric or gastrostomy tube for those patients unable to take the medicinal product by mouth.
For additional information regarding method of administration and compatibility/in-use stability studies please refer to section 6.6.
Preparation for nasogastric tube or gastrostomy tube administration
In vitro studies evaluating the percent recovery of total dose delivered with nasogastric, nasojejunal or gastrostomy tubes demonstrated the percent of dose recovered was > 99% for doses ≥ 1 ml and 70% for a 0.5 ml dose. For patients who can swallow liquids take RAVICTI should be taken orally, even those with a nasogastric and/or gastrostomy tube. However, for patients who cannot swallow liquids, a nasogastric tube or gastrostomy tube may be used to administer RAVICTI as follows:
• An oral syringe should be utilised to withdraw the prescribed dose of RAVICTI from the bottle
• The tip of the oral syringe should be placed onto the tip of the gastrostomy/nasogastric tube
• The plunger of the oral syringe should be used to administer RAVICTI into the tube
• 10 ml of water or medical formula should be used to flush the tube once, and the flush should be allowed to drain after administration
It is not recommended to administer a dose of 0.5 ml or less with nasogastric, gastrostomy or nasojejunal tubes, given the low drug recovery in dosing.
4.3 |
Ravicti 1.1 g/ml oral liquid | Clinical particulars - Contraindications | Contraindications
• Hypersensitivity to the active substance.
• Treatment of acute hyperammonaemia.
4.4 |
Ravicti 1.1 g/ml oral liquid | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Even while on treatment with glycerol phenylbutyrate, acute hyperammonaemia including hyperammonaemic encephalopathy may occur in a proportion of patients.
Reduced phenylbutyrate absorption in pancreatic insufficiency or intestinal malabsorption
Exocrine pancreatic enzymes hydrolyse glycerol phenylbutyrate in the small intestine, separating the active moiety, phenylbutyrate, from glycerol. This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion of glycerol phenylbutyrate and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Ammonia levels should be closely monitored in patients with pancreatic insufficiency or intestinal malabsorption.
Neurotoxicity
Reversible clinical manifestations suggestive of neurotoxicity (e.g., nausea, vomiting, somnolence) have been reportedly associated with phenylacetate levels ranging from 499-1,285 mcg/ml in cancer patients who received PAA intravenously. Although these have not been seen in clinical trials involving UCD patients, high PAA levels should be suspected in patients (particularly in children <2months) with unexplained somnolence, confusion, nausea and lethargy who have normal or low ammonia.
If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, measure plasma PAA and plasma PAA to PAGN, it should be considered to reduce the glycerol phenylbutyrate dose or increase the frequency of dosing if the PAA level exceeds 500 mcg/L and the plasma PAA to PAGN ratio exceeds 2.5.
Monitoring and laboratory tests
The daily dose should be individually adjusted according to the patient's estimated urea synthetic capacity, if any, amino acid profile, protein tolerance and the daily dietary protein intake needed to promote growth and development. Supplemental amino acid formulations may be necessary to maintain essential amino acids and branched chain amino acids within normal range. Further adjustment may be based on monitoring of plasma ammonia, glutamine, U-PAGN and/or plasma PAA and PAGN as well as the ratio of plasma PAA to PAGN (see section 4.2).
Potential for other medicinal products to affect ammonia
Corticosteroids
Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when corticosteroids and glycerol phenylbutyrate are used concomitantly.
Valproic acid and haloperidol
Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia levels closely when use of valproic acid or haloperidol is necessary in UCD patients.
Probenecid
Probenecid may inhibit the renal excretion of metabolites of glycerol phenylbutyrate including PAGN.
Women of childbearing potential/contraception in males and females
Effective contraceptive measures must be taken by women of child-bearing potential (see section 4.6).
Pregnancy
RAVICTI should not be used during pregnancy and in women of childbearing potential not using contraception unless the clinical condition of the woman requires treatment with glycerol phenylbutyrate, see section 4.6.
4.5 |
Ravicti 1.1 g/ml oral liquid | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Concomitant use of medicinal products known to inhibit lipase should be given with caution as glycerol phenylbutyrate is hydrolysed by digestive lipase into phenylbutyrate acid and glycerol. This may be associated with increased risk of medicinal product interactions with lipase inhibitors and with lipase contained in pancreatic enzyme replacement therapies.
A potential effect on CYP2D6 isoenzyme cannot be excluded and caution is advised for patients who receive medicinal products that are CYP2D6 substrates.
Glycerol phenylbutyrate and/or its metabolites, PAA and PBA, have been shown to be weak inducers of CYP3A4 enzyme in vivo. In vivo exposure to glycerol phenylbutyrate has resulted in decreased systemic exposure to midazolam of approximately 32% and increased exposure to the 1-hydroxy metabolite of midazolam, suggesting that steady-state dosing of glycerol phenylbutyrate results in CYP3A4 induction. The potential for interaction of glycerol phenylbutyrate as a CYP3A4 inducer and those products predominantly metabolised by the CYP3A4 pathway is possible. Therefore, therapeutic effects and/or metabolite levels of medicinal products, including some oral contraceptives that are substrates for this enzyme may be reduced and their full effects cannot be guaranteed, following co-administration with glycerol phenylbutyrate.
Other medicinal products such as corticosteroids, valproic acid, haloperidol and probenecid may have the potential to affect ammonia levels, see section 4.4.
The effects of glycerol phenylbutyrate on cytochrome P450 (CYP) 2C9 isoenzyme and potential for interaction with celecoxib has been studied in humans with no evidence of an interaction observed.
Effects of glycerol phenylbutyrate on other CYP isoenzymes have not been studied in humans and cannot be excluded.
Compatibility studies have demonstrated glycerol phenylbutyrate chemical and physical in-use stability with the following foods and nutritional supplements: apple sauce, ketchup, squash puree, and five medical formulas (Cyclinex-1, Cyclinex-2, UCD-1, UCD-2, Polycose, Pro Phree and Citrulline) typically consumed by UCD patients (see section 4.2).
4.6 |
Ravicti 1.1 g/ml oral liquid | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Women of childbearing potential/contraception in males and females
The use of RAVICTI in women of childbearing potential must be accompanied by the use of effective contraception (see section 4.4).
Pregnancy
Studies in animals have shown reproductive toxicity (see section 5.3). There are limited data regarding the use of glycerol phenylbutyrate in pregnant women.
Glycerol phenylbutyrate should not be used during pregnancy and in women of childbearing potential not using contraception unless the clinical condition of the woman requires treatment with glycerol phenylbutyrate (see section 4.4).
Breast-feeding
It is unknown whether glycerol phenylbutyrate or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from glycerol phenylbutyrate therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
Glycerol phenylbutyrate had no effect on fertility or reproductive function in male and female rats (see section 5.3). There are no data for human fertility.
4.7 |
Ravicti 1.1 g/ml oral liquid | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
RAVICTI may have major influence on the ability to drive and use machines given that treatment with glycerol phenylbutyrate may cause dizziness or headaches (see section 4.8). Patients should not drive or use machines whilst experiencing these adverse reactions.
4.8 |
Ravicti 1.1 g/ml oral liquid | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
Assessment of adverse reactions was based on exposure in 114 UCD patients (65 adults and 49 children between the ages of 2 months and 17 years) with deficiencies in CPS, OTC, ASS, ASL, ARG, or HHH across 4 short term and 3 long term clinical studies, in which 90 patients completed 12 months duration (median exposure = 51 weeks).
At the beginning of the treatment, abdominal pain, nausea, diarrhoea, and/or headache may occur; these reactions usually disappear within a few days even if treatment is continued. The most frequently reported adverse reactions (>5%) during glycerol phenylbutyrate treatment were diarrhoea, flatulence, and headache (8.8% each); decreased appetite (7.0%), vomiting (6.1%); and fatigue, nausea and, skin odour abnormal (5.3% each).
Additional adverse reactions have been evaluated in a clinical study including 16 UCD patients less than 2 months of age. The median exposure was 10 months (range 2 to 20 months).
Tabulated list of adverse reactions
The adverse reactions are listed below, by system organ class and by frequency. Frequency is defined as 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Any adverse reaction reported in one patient met the uncommon criteria. Due to the rarity of the UCD population, and the small size of the medicinal product safety population database (N=114), the adverse reaction frequency for rare and very rare is not known.
Table 1. List of adverse reactions
System organ class
Frequency
Adverse reaction
Infections and infestations
Uncommon
Gastrointestinal viral infection
Endocrine disorders
Uncommon
Hypothyroidism
Metabolism and nutrition disorders
Common
Decreased appetite, increased appetite
Uncommon
Hypoalbuminaemia, hypokalaemia
Psychiatric disorders
Common
Food aversion
Nervous system disorders
Common
Dizziness, headache, tremor
Uncommon
Dysgeusia, lethargy, paraesthesia, psychomotor hyperactivity, somnolence, speech disorder
Uncommon
Confusional state, depressed mood
Cardiac disorders
Uncommon
Ventricular arrhythmia
Vascular disorders
Uncommon
Hot flush
Respiratory, thoracic and mediastinal disorder
Uncommon
Dysphonia, epistaxis, nasal congestion, oropharyngeal pain, throat irritation
Gastrointestinal disorders
Common
Flatulence, diarrhoea, vomiting, nausea, abdominal pain, dyspepsia, abdominal distension, constipation, oral discomfort, retching
Uncommon
Abdominal discomfort, abnormal faeces, dry mouth, eructation, defaecation urgency, upper abdominal pain and/or lower abdominal pain, painful defaecation, steatorrhoea, stomatitis
Hepatobiliary disorders
Uncommon
Gallbladder pain
Skin and subcutaneous tissue disorders
Common
Abnormal skin odour, acne
Uncommon
Alopecia, hyperhidrosis, pruritic rash
Musculoskeletal and connective tissue disorders
Uncommon
Back pain, joint swelling, muscle spasm, pain in extremity, plantar fasciitis
Renal and urinary disorders
Uncommon
Bladder pain
Reproductive system and breast disorders
Common
Metrorrhagia
Uncommon
Amenorrhoea, irregular menstruation
General disorders and administration site conditions
Common
Fatigue, oedema peripheral
Uncommon
Hunger, pyrexia
Investigations
Common
Increased aspartate aminotransferase, alanine aminotransferase increased, increased anion gap, decreased lymphocyte count, decreased vitamin D
Uncommon
Blood potassium increased, blood triglycerides increased, electrocardiogram abnormal, low density lipoprotein increased, prothrombin time prolonged, white blood cell count increased, weight increased, weight decreased
Paediatric population
Adverse reactions reported in more paediatric than adult patients during long-term treatment with glycerol phenylbutyrate included upper abdominal pain (3 of 49 paediatric [6.1%] versus 1 of 51 adults [2.0%] and increased anion gap (2 of 49 paediatric [4.1%] versus 0 of 51 adults [0%].
In an additional long term (24 month), uncontrolled, open-label clinical study the safety of RAVICTI has been evaluated in 16 UCD patients less than 2 months of age and 10 paediatric patients with UCDs aged 2 months to less than 2 years. The median exposure was 10 months (range 2 to 20 months) and median exposure in the 2 months to less than 2 years of age was 9 months (range 0.2 to 20.3 months). Adverse reactions are summarized below.
Table 2. List of adverse reactions in patients less than 2 months of age
System organ class
Preferred Term
Total
(N=16)
Blood and lymphatic system disorders
2 (12.5%)
Anaemia,
1 (6.3%)
Thrombocytosis
1 (6.3%)
Metabolism and nutrition disorders
1 (6.3%)
Hypophagia
1 (6.3%)
Gastrointestinal disorders
3 (18.8%)
Diarrhoea,
2 (12.5%)
Constipation
1 (6.3%)
Flatulence
1 (6.3%)
Gastrooesophageal reflux disease
1 (6.3%)
Skin and subcutaneous tissue disorders
3(18.8%)
Rash
3(18.8%)
Investigations
4 (25%)
Amino acid level decreased
1 (6.3%)
Gamma-glutamyltransferase increased
1 (6.3%)
Hepatic enzyme increased
1 (6.3%)
Transaminases increased
1 (6.3%)
Table 3. List of adverse reactions in patients 2 months to less than 2 years of age
System Organ Class
Preferred Term
Total
(N=10)
Gastrointestinal disorders
2 (20%)
Constipation
1 (10%)
Diarrhoea
1 (10%)
Skin and subcutaneous tissue disorders
2 (20%)
Eczema
1 (10%)
Nail ridging
1 (10%)
Rash
1 (10%)
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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Ravicti 1.1 g/ml oral liquid | Clinical particulars - Overdose | Overdose
PAA, the active metabolite of glycerol phenylbutyrate, is associated with signs and symptoms of neurotoxicity (see section 4.4) and could accumulate in patients who receive an overdose. In case of overdose, the medicinal product should be discontinued and the patient monitored for any signs or symptoms of adverse reactions.
5. Pharmacological properties
5.1 |
Ravicti 1.1 g/ml oral liquid | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
RAVICTI is a pro-drug of PBA. Upon oral ingestion, PBA is released from the glycerol backbone in the gastrointestinal tract by pancreatic lipases. PBA derived from glycerol phenylbutyrate is further converted by β-oxidation to PAA.
In healthy, fasting adult subjects receiving a single oral dose of 2.9 ml/m2 of glycerol phenylbutyrate, peak plasma levels of PBA, PAA, and PAGN occurred at 2 h, 4 h, and 4 h, respectively. Upon single-dose administration of glycerol phenylbutyrate, plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time post dose (0.25 h). Mean maximum concentration (Cmax) for PBA, PAA, and PAGN was 37.0 micrograms/ml, 14.9 micrograms/ml, and 30.2 micrograms/ml, respectively. In healthy subjects, intact glycerol phenylbutyrate was not detected in plasma.
In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose dependent manner. Following 4 ml of glycerol phenylbutyrate for 3 days (3 times a day [TID]), mean Cmax and AUC were 66 mcg/ml and 930 mcg•h/ml for PBA and 28 microgram /ml and 942 mcg•h/ml for PAA, respectively. In the same study, following 6 ml of glycerol phenylbutyrate for 3 days (TID), mean Cmax and AUC were 100 mcg/ml and 1,400 mcg•h/ml for PBA and 65 mcg/ml and 2,064 mcg•h/ml for PAA, respectively.
In adult UCD patients receiving multiple doses of glycerol phenylbutyrate, maximum plasma concentrations at steady state (Cmax, ss) of PBA, PAA, and PAGN occurred at 8 h, 12 h, and 10 h, respectively, after the first dose in the day. Intact glycerol phenylbutyrate was not detectable in plasma in UCD patients.
Population pharmacokinetic modelling and dosing simulations suggest that PBA enters the circulation about 70-75% more slowly when given orally as glycerol phenylbutyrate as compared with sodium phenylbutyrate and further indicate that body surface area is the most significant covariate explaining the variability of PAA clearance.
Distribution
In vitro, the extent of human plasma protein binding for 14C-labeled metabolites was 80.6% to 98.0% for PBA (over 1-250 microgram/ml), and 37.1% to 65.6% for PAA (over 5-500 microgram/ml). The protein binding for PAGN was 7% to 12% and no concentration effects were noted.
Biotransformation
Upon oral administration, pancreatic lipases hydrolyse glycerol phenylbutyrate and release PBA. PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: Lglutamine- N-acetyltransferase to form PAGN. PAGN is subsequently eliminated in the urine.
Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases in the ratio of plasma PAA to PAGN with increasing dose and with increasing severity of hepatic impairment.
In healthy subjects, after administration of 4 ml, 6 ml, and 9 ml 3 times daily for 3 days, the ratio of mean AUC0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively. In a separate study, in patients with hepatic impairment (Child-Pugh B and C), the ratios of mean values for PAA to PAGN among all patients dosed with 6 ml and 9 ml twice daily ranged from 0.96 to 1.28 and for patients dosed with 9 ml twice daily ranged from 1.18-3.19.
In in vitro studies, the specific activity of lipases for glycerol phenylbutyrate was seen in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase–related protein 2. Further, glycerol phenylbutyrate was hydrolysed in vitro by esterases in human plasma. In these in vitro studies, a complete disappearance of glycerol phenylbutyrate did not produce molar equivalent PBA, suggesting the formation of mono- or bis-ester metabolites. However, the formation of mono- or bis-esters was not studied in humans.
Elimination
The mean (SD) percentage of administered PBA eliminated as PAGN was approximately 68.9% (17.2) in adults and 66.4% (23.9) in paediatric UCD patients at steady state. PAA and PBA represented minor urinary metabolites, each accounting for <1% of the administered dose of PBA.
Special populations
Hepatic impairment
In a study in patients with clinically decompensated cirrhosis and hepatic encephalopathy (Child-Pugh B and C), mean Cmax of PAA was 144 mcg/ml (range: 14-358 mcg/ml) after daily dosing of 6 ml of glycerol phenylbutyrate twice daily, while mean Cmax of PAA was 292 mcg/ml (range: 57-655 mcg/ml) after daily dosing of 9 ml of glycerol phenylbutyrate twice daily. The ratio of mean values for PAA to PAGN among all patients dosed with 6 ml BID ranged from 0.96 to 1.28 and for patients dosed with 9 ml twice daily ranged from 1.18-3.19. After multiple doses, a PAA concentration >200 mcg/L was associated with a ratio of plasma PAA to PAGN concentrations higher than 2.5.
These findings collectively indicate that conversion of PAA to PAGN may be impaired in patients with severe hepatic impairment and that a plasma PAA to PAGN ratio > 2.5 identifies patients at risk of elevated PAA levels.
Renal impairment
The pharmacokinetics of glycerol phenylbutyrate in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on haemodialysis, have not been studied.
Gender
In healthy adult volunteers, a gender effect was found for all metabolites, with women generally having higher plasma concentrations of all metabolites than men at a given dose level. In healthy female volunteers, mean Cmax for PAA was 51% and 120% higher than in male volunteers after administration of 4 ml and 6 ml 3 times daily for 3 days, respectively. The dose normalized mean AUC0-23h for PAA was 108% higher in females than in males. However, dosing in UCD patients must be individualized based on the specific metabolic needs and residual enzyme capacity of the patient, irrespective of gender.
Paediatric population
Population pharmacokinetic modelling and dosing simulations suggest body surface area is the most significant covariate explaining the variability of PAA clearance. PAA clearance was 7.1 L/h, 10.9 L/h, 16.4 L/h, and 24.4 L/h, respectively, for UCD patients ages ≤ 2, 3 to 5, 6 to 11, and 12 to 17 years. In 16 paediatric UCD patients aged less than 2 months, PAA clearance was 3.8 L/h. In 7 paediatric patients aged 2 months to under 2 years of age who received RAVICTI for up to 12 months, the concentrations of PAA, PBA, and PAGN did not increase over the treatment period and the overall median PAA, PBA, and PAGN concentrations in these patients were similar to those observed in older paediatric age groups.
The mean peak ratio of PAA to PAGN in UCD patients aged birth to less than 2 months was higher (mean: 1.65; range 0.14 to 7.07) than for UCD patients aged 2 months to less than 2 years (mean 0.59; range 0.17 to 1.21). No PAA toxicity was observed in the subjects age < 2 months.
5.3 |
Ravicti 1.1 g/ml oral liquid | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Carcinogenesis
In a rat study, glycerol phenylbutyrate caused a statistically significant increase in the incidence of pancreatic acinar cell adenoma, carcinoma, and combined adenoma or carcinoma in males and females, at a dose of 4.7 and 8.4 times the dose in adult patients, (6.87 ml/m2/day based on combined AUCs for PBA and PAA). The incidence of the following tumours was also increased in female rats: thyroid follicular cell adenoma, carcinoma and combined adenoma or carcinoma, adrenal cortical combined adenoma or carcinoma, cervical schwannoma, uterine endometrial stromal polyp, and combined polyp or sarcoma.
Glycerol phenylbutyrate was not tumourigenic at doses up to 1,000 mg/kg/day in a 26 week mouse study.
Glycerol phenylbutyrate has been tested in a range of in vitro and in vivo genotoxicity studies, and shown no genotoxic activity.
Impairment of fertility
Glycerol phenylbutyrate had no effect on fertility or reproductive function in male and female rats at clinical exposure levels, however at oral doses up to approximately 7 times the dose in adult patients, maternal as well as male toxicity was observed and the number of nonviable embryos was increased.
Development studies
Oral administration of glycerol phenylbutyrate during the period of organogenesis in rats and rabbits had no effects on embryo-foetal development at 2.7 and 1.9 times the dose in adult patients, respectively. However, maternal toxicity and adverse effects on embryo-foetal development including reduced foetal weights and cervical ribs were observed in a rat study with a dose approximately 6 times the dose in adult patients, based on combined AUCs for PBA and PAA. No developmental abnormalities were observed in rats through day 92 postpartum following oral administration in pregnant rats, during organogenesis and lactation.
Juvenile animal study
In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating and pregnancy after maturation, terminal body weight was dose-dependently reduced in males and females, by up to 16% and 12% respectively. Fertility (number of pregnant rats) was decreased by up to 25%, at a dose of 2.6 times the dose in adult patients. Embryo toxicity (increased resorptions) and reduced litter size was also observed.
6. |
Ravicti 1.1 g/ml oral liquid | Pharmaceutical particulars - List of excipients | List of excipients
None.
6.2 |
Ravicti 1.1 g/ml oral liquid | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Ravicti 1.1 g/ml oral liquid | Pharmaceutical particulars - Shelf life | Shelf life
2 years.
After the first opening of the bottle, the medicinal product must be used within 14 days and the bottle and its contents discarded, even if not empty.
6.4 |
Ravicti 1.1 g/ml oral liquid | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Ravicti 1.1 g/ml oral liquid | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Clear, Type III glass, bottle with a high density polyethylene (HDPE) child-resistant closure with integrated syringe insert.
Each bottle contains 25 ml of liquid.
Pack size: 1 bottle.
6.6 |
Ravicti 1.1 g/ml oral liquid | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with national requirements.
Based on prescribed dosing volume, patients should be advised to obtain CE marked oral syringes with suitable size for the dose and compatible with the syringe insert in the bottle from the pharmacy.
One oral syringe should be used each day. The oral syringe should not be rinsed between daily doses as the introduction of water causes glycerol phenylbutyrate to degrade. The oral syringe should be discarded after the last dose of each day.
Chemical compatibility of glycerol phenylbutyrate with medical grade silicone nasogastric, gastrostomy, and nasojejunal tubes has been demonstrated. In vitro studies evaluating the percent recovery of total dose delivered with nasogastric or gastrostomy tubes demonstrated the percent of dose recovered was >99% for doses > 1 ml and 70% for a 0.5 ml dose. Therefore, it is recommended that nasogastric, nasojejunal or gastrostomy tubes only be used to administer doses ≥ 1 ml. If there is a need to administer a dose of 0.5 ml or less with such nasogastric, gastrostomy or nasojejunal tubes, consideration should be given to the low drug recovery in dosing.
7. |
Ravicti 1.1 g/ml oral liquid | Marketing authorisation holder | Immedica Pharma AB
SE-113 63 Stockholm
Sweden
8. Marketing authorisation number(s)
GBPL 53487/0001
9. |
Ravicti 1.1 g/ml oral liquid | Date of first authorisation/renewal of the authorisation | 01/01/2021
10. |
Ravicti 1.1 g/ml oral liquid | Date of revision of the text | 01/10/2022 |
Raxone 150 mg film-coated tablets | Name of the medicinal product | Raxone 150 mg film-coated tablets
2. |
Raxone 150 mg film-coated tablets | Qualitative and quantitative composition | Each film-coated tablet contains 150 mg idebenone.
Excipients with known effect
Each film-coated tablet contains 46 mg of lactose (as monohydrate) and 0.23 mg of sunset yellow FCF (E110).
For the full list of excipients, see section 6.1.
3. |
Raxone 150 mg film-coated tablets | Pharmaceutical form | Film-coated tablet.
Orange, round, biconvex film-coated tablet of 10 mm diameter, engraved with the Santhera logo on one side and '150' on the other side.
4. |
Raxone 150 mg film-coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Raxone is indicated for the treatment of visual impairment in adolescent and adult patients with Leber's Hereditary Optic Neuropathy (LHON) (see section 5.1).
4.2 |
Raxone 150 mg film-coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The recommended dose is 900 mg/day idebenone (300 mg, 3 times a day).
Data regarding continuous treatment with idebenone for up to 24 months are available as part of a Natural History controlled open label clinical trial (see section 5.1).
Special populations
Elderly
No specific dose adjustment is required for the treatment of LHON in elderly patients.
Hepatic or renal impairment
Patients with hepatic or renal impairment have been investigated. However, no specific posology recommendations can be made. Caution is advised in treatment of patients with hepatic or renal impairment, since adverse events have resulted in temporary interruption or discontinuation of treatment (see section 4.4).
In the absence of sufficient clinical data, caution should be exercised in patients with renal impairment.
Paediatric population
The safety and efficacy of Raxone in LHON patients under 12 years of age have not yet been established. Currently available data are described in sections 5.1 and 5.2, but no recommendation on posology can be made.
Method of administration
Raxone film-coated tablets should be swallowed whole with water. The tablets should not be broken or chewed. Raxone should be administered with food because food increases the bioavailability of idebenone.
4.3 |
Raxone 150 mg film-coated tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 |
Raxone 150 mg film-coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Monitoring
Patients should be regularly monitored according to local clinical practice.
Hepatic or renal impairment
Caution should be exercised when prescribing Raxone to patients with hepatic or renal impairment. Adverse events have been reported in patients with hepatic impairment, which have resulted in temporary interruption or discontinuation of treatment.
Chromaturia
The metabolites of idebenone are coloured and may cause chromaturia, i.e. a reddish-brown discoloration of the urine. This effect is harmless, not associated with haematuria, and does not require any adaptation of dose or discontinuation of treatment.
Caution should be exercised to ensure that the chromaturia does not mask changes of colour due to other reasons (e.g. renal or blood disorders).
Lactose
Raxone contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Raxone.
Sunset yellow
Raxone contains sunset yellow (E110) which may cause allergic reactions.
4.5 |
Raxone 150 mg film-coated tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Data from in vitro studies have demonstrated that idebenone and its metabolite QS10 do not exert systemic inhibition of cytochrome P450 isoforms CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 at clinically relevant concentrations of idebenone or QS10. In addition, no induction of CYP1A2, CYP2B6 or CYP3A4 was observed.
In vivo idebenone is a mild inhibitor of CYP3A4. Data from a drug-drug interaction study in 32 healthy volunteers indicate that on the first day of oral administration of 300 mg idebenone t.i.d., the metabolism of midazolam, a CYP3A4 substrate, was not modified when both medicinal products were administered together. After repeated administration Cmax and AUC of midazolam were increased by 28% and 34%, respectively, when midazolam was administered in combination with 300 mg idebenone t.i.d. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving idebenone.
Idebenone may inhibit P-glycoprotein (P-gp) with possible exposure increases of, e.g., dabigatran etexilate, digoxin or aliskiren. These medicines should be administered with caution in patients receiving idebenone. Idebenone is not a substrate for P-gp in vitro.
4.6 |
Raxone 150 mg film-coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
The safety of idebenone in pregnant women has not been established. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Idebenone should only be administered to pregnant women or women of child-bearing potential likely to become pregnant if it is considered that the benefit of the therapeutic effect outweighs any potential risk.
Breast-feeding
Available pharmacodynamic/toxicological data in animals have shown excretion of idebenone in milk (for details see 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Raxone therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
There are no data concerning the effect of exposure to idebenone on human fertility.
4.7 |
Raxone 150 mg film-coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Raxone has no or negligible influence on the ability to drive and use machines.
4.8 |
Raxone 150 mg film-coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions to idebenone are mild to moderate diarrhoea (usually not requiring the discontinuation of the treatment), nasopharyngitis, cough and back pain.
Tabulated list of adverse reactions
The following adverse reactions emerging from clinical trials in LHON patients or reported post-marketing in other indications are tabulated below. Frequency groupings are defined to the following convention: very common (≥1/10), common (≥1/100 to <1/10), not known (cannot be estimated from the available data).
System Organ Class
Preferred Term
Frequency
Infections and Infestations
Nasopharyngitis
Very common
Bronchitis
Not known
Blood and lymphatic system disorders
Agranulocytosis, anaemia, leukocytopenia, thrombocytopenia, neutropenia
Not known
Metabolism and nutrition disorders
Blood cholesterol increased, blood triglycerides increased
Not known
Nervous system disorders
Seizure, delirium, hallucinations, agitation, dyskinesia, hyperkinesia, poriomania, dizziness, headache, restlessness, stupor
Not known
Respiratory, thoracic and mediastinal disorders
Cough
Very common
Gastrointestinal disorders
Diarrhoea
Common
Nausea, vomiting, anorexia, dyspepsia
Not known
Hepatobiliary disorders
Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, gamma-glutamyltransferase increased, blood bilirubin increased, hepatitis
Not known
Skin and subcutaneous tissue disorders
Rash, pruritus
Not known
Musculoskeletal and connective tissue disorders
Back pain
Common
Pain in extremity
Not known
Renal and urinary disorders
Azotaemia, chromaturia
Not known
General disorders and administration site conditions
Malaise
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:
Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Raxone 150 mg film-coated tablets | Clinical particulars - Overdose | Overdose
No report of overdose has been received from the RHODOS, the LEROS and the PAROS studies. Doses up to 2,250 mg/day have been administered in clinical studies showing a safety profile consistent with that reported in section 4.8.
There is no specific antidote for idebenone. When needed, supportive symptomatic treatment should be given.
5. Pharmacological properties
5.1 |
Raxone 150 mg film-coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
Food increases the bioavailability of idebenone by approximately 5-7-fold and therefore, Raxone should always be administered with food. The tablets should not be broken or chewed.
After oral administration of Raxone, idebenone is rapidly absorbed. On repeat dosing, maximum plasma concentrations of idebenone are reached on average within 1 hour (median 0.67 h range: 0.33-2.00 h).
Distribution
Experimental data have shown that idebenone passes the blood-brain barrier and is distributed at significant concentrations in cerebral tissue. Following oral administration pharmacologically relevant concentrations of idebenone are detectable in the aqueous humor of the eye.
Biotransformation
Metabolism occurs by means of oxidative shortening of the side chain and by reduction of the quinone ring and conjugation to glucuronides and sulphates. Idebenone shows a high first pass metabolism resulting in conjugates of idebenone (glucuronides and sulphates (IDE-C)) and the Phase I metabolites QS10, QS6, and QS4 as well as their corresponding Phase II metabolites (glucuronides and sulphates (QS10+QS10-C, QS6+QS6-C, QS4+QS4-C)). The main metabolites in plasma are IDE-C and QS4+QS4-C.
Elimination
Due to the high first-pass effect, the plasma concentrations of idebenone were generally only measurable up to 6 hours after oral administration of 750 mg Raxone, given either as a single oral dose or after repeated (14 days) t.i.d dosing. The main route of elimination is metabolism, with the majority of dose excreted via the kidneys as metabolites. After a single or repeated oral dose of 750 mg Raxone, QS4+QS4-C were the most prominent idebenone-derived metabolites in urine, representing on average between 49.3% and 68.3% of the total administered dose. QS6+QS6 represented 6.45% to 9.46%, whereas QS10+QS10-C and IDE+IDE-C were close to 1% or below.
Linearity/non-linearity
In phase I pharmacokinetic studies, proportional increases in plasma concentrations of idebenone were observed for doses from 150 mg to 1050 mg. Neither idebenone nor its metabolites showed time-dependent pharmacokinetics.
Hepatic or renal impairment
No data are available in these populations.
Paediatric population
Whilst clinical trials experience in paediatrics with LHON is limited to patients of 14 years of age and above, pharmacokinetic data from population pharmacokinetic studies, which included paediatric Friedreich's Ataxia patients of age 8 years and above, did not reveal any significant differences in the pharmacokinetics of idebenone.
5.3 |
Raxone 150 mg film-coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
6. |
Raxone 150 mg film-coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Lactose monohydrate
Cellulose, microcrystalline
Croscarmellose sodium
Povidone (K25)
Magnesium stearate
Silica, colloidal anhydrous
Film-coating
Macrogol (3350)
Poly(vinyl alcohol)
Talc
Titanium dioxide
Sunset yellow FCF (E110)
6.2 |
Raxone 150 mg film-coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Raxone 150 mg film-coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
5 years.
6.4 |
Raxone 150 mg film-coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Raxone 150 mg film-coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
White high-density polyethylene bottles with white polypropylene child-resistant tamper-evident twist-off caps containing 180 film-coated tablets.
6.6 |
Raxone 150 mg film-coated tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Raxone 150 mg film-coated tablets | Marketing authorisation holder | Chiesi Ltd
Manchester Green
333 Styal Road
Manchester
M22 5LG
United Kingdom
8. Marketing authorisation number(s)
PLGB 08829/0204
9. |
Raxone 150 mg film-coated tablets | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 1 January 2021
10. |
Raxone 150 mg film-coated tablets | Date of revision of the text | 10/2022 |
Reagila 1.5 mg hard capsules | Name of the medicinal product | Reagila 1.5 mg hard capsules
Reagila 3 mg hard capsules
Reagila 4.5 mg hard capsules
Reagila 6 mg hard capsules
2. |
Reagila 1.5 mg hard capsules | Qualitative and quantitative composition | Reagila 1.5 mg hard capsules
Each hard capsule contains cariprazine hydrochloride corresponding to 1.5 mg cariprazine.
Reagila 3 mg hard capsules
Each hard capsule contains cariprazine hydrochloride corresponding to 3 mg cariprazine.
Excipient with known effect
Each hard capsule contains 0.0003 mg Allura red AC (E 129).
Reagila 4.5 mg hard capsules
Each hard capsule contains cariprazine hydrochloride corresponding to 4.5 mg cariprazine.
Excipient with known effect
Each hard capsule contains 0.0008 mg Allura red AC (E 129).
Reagila 6 mg hard capsules
Each hard capsule contains cariprazine hydrochloride corresponding to 6 mg cariprazine.
Excipient with known effect
Each hard capsule contains 0.0096 mg Allura red AC (E 129).
For the full list of excipients, see section 6.1.
3. |
Reagila 1.5 mg hard capsules | Pharmaceutical form | Hard capsule
Reagila 1.5 mg hard capsules
'Size 4' (approximately 14.3 mm in length) hard gelatin capsule with white opaque cap and white opaque body imprinted with “GR 1.5” on the capsule body with black ink. The capsules are filled with white to yellowish white powder mixture.
Reagila 3 mg hard capsules
'Size 4' (approximately 14.3 mm in length) hard gelatin capsule with green opaque cap and white opaque body imprinted with “GR 3” on the capsule body with black ink. The capsules are filled with white to yellowish white powder mixture.
Reagila 4.5 mg hard capsules
'Size 4' (approximately 14.3 mm in length) hard gelatin capsule with green opaque cap and green opaque body imprinted with “GR 4.5” on the capsule body with white ink. The capsules are filled with white to yellowish white powder mixture.
Reagila 6 mg hard capsules
'Size 3' (approximately 15.9 mm in length) hard gelatin capsule with purple opaque cap and white opaque body imprinted with “GR 6” on the capsule body with black ink. The capsules are filled with white to yellowish white powder mixture.
4. |
Reagila 1.5 mg hard capsules | Clinical particulars - Therapeutic indications | Therapeutic indications
Reagila is indicated for the treatment of schizophrenia in adult patients.
4.2 |
Reagila 1.5 mg hard capsules | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The recommended starting dose of cariprazine is 1.5 mg once daily. Thereafter the dose can be increased slowly in 1.5 mg increments to a maximum dose of 6 mg/day, if needed. The lowest effective dose should be maintained according to the clinical judgement of the treating physician. Because of the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Patients should be monitored for adverse reactions and treatment response for several weeks after starting cariprazine and after each dose change (see section 5.2).
Switching from other antipsychotics to cariprazine
When switching from another antipsychotic to cariprazine gradual cross-titration should be considered, with gradual discontinuation of the previous treatment while cariprazine treatment is initiated.
Switching to another antipsychotic from cariprazine
When switching to another antipsychotic from cariprazine, no gradual cross-titration is needed, the new antipsychotic should be initiated in its lowest dose while cariprazine is discontinued. It should be considered that plasma concentration of cariprazine and its active metabolites will decline by 50% in ~1 week (see section 5.2).
Missed dose
If the patient misses a dose, the patient should take the missed dose as soon as possible. However, if it is almost time for the next dose, the missed dose should be skipped and the next dose should be taken according to the regular schedule. It is not recommended to take a double dose to make up for the forgotten dose.
Special population
Renal impairment
No dose adjustment is required in patients with mild to moderate renal impairment (Creatinine Clearance (CrCl) ≥ 30 mL/min and < 89 mL/min). Safety and efficacy of cariprazine have not been evaluated in patients with severe renal impairment (CrCl < 30 mL/min). Use of cariprazine is not recommended in patients with severe renal impairment (see section 5.2).
Hepatic impairment
No dose adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5-9). Safety and efficacy of cariprazine have not been evaluated in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). Use of cariprazine is not recommended in patients with severe hepatic impairment (see section 5.2).
Elderly
Available data in elderly patients aged ≥ 65 years treated with cariprazine are not sufficient to determine whether or not they respond differently from younger patients (see section 5.2). Dose selection for an elderly patient should be more cautious.
Paediatric population
The safety and efficacy of cariprazine in children and adolescents aged less than 18 years have not been established. No data are available.
Method of administration
Reagila is for oral use, to be taken once daily at the same time of the day with or without food.
Alcohol should be avoided when taking cariprazine (see section 4.5).
4.3 |
Reagila 1.5 mg hard capsules | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concomitant administration of strong or moderate CYP3A4 inhibitors (see section 4.5).
Concomitant administration of strong or moderate CYP3A4 inducers (see section 4.5).
4.4 |
Reagila 1.5 mg hard capsules | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Suicidal ideation and behaviour
The possibility of suicidality (suicidal ideation, suicide attempt and completed suicide) is inherent in psychotic illnesses and, generally, it is reported early after initiation or switch of antipsychotic therapy. Close supervision of high-risk patients should accompany antipsychotic therapy.
Akathisia, restlessness
Akathisia and restlessness is a frequently occurring adverse reaction of antipsychotics. Akathisia is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. As cariprazine causes akathisia and restlessness, it should be used cautiously in patients who are prone to or already exhibit symptoms of akathisia. Akathisia develops early in treatment. Therefore close monitoring in the first phase of treatment is important. Prevention includes slow up-titration; treatment measures include slight down-titration of cariprazine or anti-EPS medicinal product The dose can be modified based on individual response and tolerability (see section 4.8).
Tardive dyskinesia
Tardive dyskinesia is a syndrome consisting of potentially irreversible, rhythmical, involuntary movements, predominantly of the tongue and/or face that can develop in patients treated with antipsychotics. If signs and symptoms of tardive dyskinesia appear in a patient treated with cariprazine, discontinuation should be considered.
Parkinson's disease
If prescribed to patients with Parkinson's disease, antipsychotic medicinal products may exacerbate the underlying disease and worsen symptoms of Parkinson's disease. Physicians should, therefore, weigh the risks versus the benefits when prescribing cariprazine to patients with Parkinson's disease.
Ocular symptoms/cataract
In the preclinical studies of cariprazine lens opacity/cataract was detected in dogs (see sections 4.8 and 5.3). However, a causal relationship between lenticular changes / cataracts observed in human studies and cariprazine use has not been established. Nevertheless, patients who would develop symptoms potentially related to cataract should be advised to ophthalmologic examination and re-evaluated for treatment continuation.
Neuroleptic malignant syndrome (NMS)
A potentially fatal symptom complex referred to as NMS has been reported in association with antipsychotic treatment. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, elevated serum creatine phosphokinase levels, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, cariprazine must be discontinued immediately.
Seizures and convulsions
Cariprazine should be used cautiously in patients with history of seizures or with conditions that potentially lower the seizure threshold.
Elderly patients with dementia
Cariprazine has not been studied in elderly patients with dementia and is not recommended to treat elderly patients with dementia due to increased risk of overall mortality.
Risk of cerebrovascular accidents (CVA)
An approximately 3-fold increased risk of CVA has been seen in randomised placebo-controlled clinical studies in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Cariprazine should be used with caution in patients with risk factors for stroke.
Cardiovascular disorders
Blood pressure changes
Cariprazine can cause orthostatic hypotension as well as hypertension (see section 4.8). Cariprazine should be used with caution in patients with known cardiovascular disease predisposing to blood pressure changes. Blood pressure should be monitored.
Electrocardiogram (ECG) changes
QT prolongation can develop in patients treated with antipsychotics.
With cariprazine no QT interval prolongation was detected compared to placebo in a clinical study designed to assess QT prolongation (see section 5.1). In clinical studies, only a few, non-serious, QT-prolongations have been reported with cariprazine (see section 4.8). Therefore, cariprazine should be used cautiously in patients with known cardiovascular disease or in patients with a family history of QT prolongation and in patients treated with medicinal products that might cause QT prolongation (see section 5.1).
Venous thromboembolism (VTE)
Cases of VTE have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with cariprazine and preventive measures undertaken.
Hyperglycaemia and diabetes mellitus
Patients with an established diagnosis of diabetes mellitus or patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should be monitored for serum glucose levels. In clinical studies, glucose-related adverse reactions have been reported with cariprazine (see section 5.1).
Weight change
Significant weight gain has been observed with the use of cariprazine. Patients should have their weight monitored regularly (see section 4.8).
Excipients
Reagila 3 mg, 4.5 mg and 6 mg hard capsules contain Allura red AC (E 129), which may cause allergic reactions.
4.5 |
Reagila 1.5 mg hard capsules | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Potential for other medicinal products to affect cariprazine
Metabolism of cariprazine and its major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), is mediated mainly by CYP3A4 with a minor contribution of CYP2D6.
CYP3A4 inhibitors
Ketoconazole, a strong CYP3A4 inhibitor, caused two-fold increase in plasma exposure for total cariprazine (sum of cariprazine and its active metabolites) during short-term (4 days) co-administration, either if unbound or unbound+bound moieties considered.
Due to the long half-life of the active moieties of cariprazine a further increase in plasma exposure of total cariprazine can be expected during longer co-administration. Therefore, co-administration of cariprazine with strong or moderate inhibitors of CYP3A4 (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole, verapamil) is contraindicated (see section 4.3). Consumption of grapefruit juice should be avoided.
CYP3A4 inducers
Co-administration of cariprazine with strong and moderate inducers of CYP3A4 may result in a significant decrease in total cariprazine exposure, therefore the co-administration of cariprazine and strong or moderate CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated (see section 4.3).
CYP2D6 inhibitors
CYP2D6 mediated pathway plays a minor role in the metabolism of cariprazine, the major pathway is via CYP3A4 (see section 5.2). Therefore CYP2D6 inhibitors are unlikely to have a clinically relevant effect on cariprazine metabolism.
Potential for cariprazine to affect other medicinal products
P-glycoprotein (P-gp) substrates
Cariprazine is a P-gp inhibitor in vitro at its theoretical maximum intestinal concentration. The clinical consequences of this effect is not fully understood, however the use of P-gp substrates with narrow therapeutic index such as dabigatran and digoxin could require extra monitoring and dose adjustment.
Hormonal contraceptives
In a drug interaction study, 28 days of treatment with cariprazine at 6 mg daily had no clinically relevant effect on the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel).
Pharmacodynamic interactions
Given the primary central nervous system effects of cariprazine, Reagila should be used with caution in combination with other centrally acting medicinal products and alcohol.
4.6 |
Reagila 1.5 mg hard capsules | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Women of childbearing potential/Contraception
Women of childbearing potential must be advised to avoid pregnancy while on Reagila. Female patients of child-bearing potential must use highly effective contraceptive methods during treatment and for at least 10 weeks following the last dose of Reagila.
Pregnancy
There are no or limited amount of data from the use of cariprazine in pregnant women.
Studies in animals have shown reproductive toxicity including developmental malformations in rats (see section 5.3).
Reagila is not recommended during pregnancy and in women of childbearing potential not using effective contraception. After discontinuation of cariprazine treatment contraception should be used for at least 10 weeks due to the slow elimination of active moieties.
Neonates exposed to antipsychotics (including cariprazine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress or feeding disorder. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases, neonates have required intensive care unit support and prolonged hospitalization. Consequently, newborns should be monitored carefully.
Breast-feeding
It is unknown whether cariprazine or its major active metabolites are excreted in human milk. Cariprazine and its metabolites are excreted in milk of rats during lactation (see section 5.3). A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with cariprazine.
Fertility
The effect of cariprazine on human fertility has not been evaluated. In rat studies lower female fertility and conception indices were observed (see section 5.3).
4.7 |
Reagila 1.5 mg hard capsules | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Cariprazine has minor or moderate influence on the ability to drive and use machines. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with Reagila does not affect them adversely.
4.8 |
Reagila 1.5 mg hard capsules | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
The most frequently reported adverse drug reactions (ADRs) with cariprazine in the dose range (1.5-6 mg) were akathisia (19%) and parkinsonism (17.5%). Most events were mild to moderate in severity.
Tabulated list of adverse reactions
ADRs based upon pooled data from cariprazine schizophrenia studies are shown by system organ class and by preferred term in Table 1.
Adverse reactions are ranked by frequency, the most frequent first, using the following convention: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1 Adverse drug reactions occurring in patients with schizophrenia
MedDRA
System Organ Class
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)
Frequency not known
Blood and lymphatic system disorders
Anaemia
Eosinophilia
Neutropenia
Immune system disorders
Hypersensitivity
Endocrine disorders
Blood thyroid stimulating hormone decreased
Hypothyroidism
Metabolism and nutrition disorders
Dyslipidaemia
Weight increased
Decreased appetite
Increased appetite
Blood sodium abnormal
Diabetes mellitus
Blood glucose increased
Psychiatric disorders
Sleep disorders1
Anxiety
Suicidal behaviour
Delirium
Depression
Libido decreased
Libido increased
Erectile dysfunction
Nervous system disorders
Akathisia2
Parkinsonism3
Sedation
Dizziness
Dystonia4
Other extrapyramidal diseases and abnormal movement disorders5
Tardive dyskinesia
Dyskinesia6
Dysaesthesia
Lethargy
Seizures/ Convulsion
Amnesia
Aphasia
Neuroleptic malignant syndrome
Eye disorders
Vision blurred
Intraocular pressure increased
Accommodation disorder
Visual acuity reduced
Eye irritation
Cataract Photophobia
Ear and labyrinth disorders
Vertigo
Cardiac disorders
Tachyarrhythmia
Cardiac conduction disorders
Bradyarrhythmia
Electrocardiogram QT prolonged
Electrocardiogram T wave abnormal
Vascular disorders
Hypertension
Hypotension
Respiratory, thoracic and mediastinal disorders
Hiccups
Gastrointestinal disorders
Vomiting
Nausea
Constipation
Gastrooesophageal reflux disease
Dysphagia
Hepatobiliary disorders
Hepatic enzymes increased
Blood bilirubin increased
Toxic hepatitis
Skin and subcutaneous tissue disorders
Pruritus
Rash
Musculoskeletal and connective tissue disorders
Blood creatine phosphokinase increased
Rhabdomyolysis
Renal and urinary disorders
Dysuria Pollakisuria
Pregnancy, puerperium and perinatal conditions
Drug withdrawal syndrome neonatal (see section 4.6)
General disorders and administration site conditions
Fatigue
Thirst
1Sleep disorders: Insomnia, Abnormal dreams/nightmare, Circadian rhythm sleep disorder, Dyssomnia, Hypersomnia, Initial insomnia, Middle insomnia, Nightmare, Sleep disorder, Somnambulism, Terminal insomnia
2Akathisia: Akathisia, Psychomotor hyperactivity, Restlessness
3Parkinsonism: Akinesia, Bradykinesia, Bradyphrenia, Cogwheel rigidity, Extrapyramidal disorder, Gait disturbance, Hypokinesia, Joint stiffness, Tremor, Masked facies, Muscle rigidity, Musculoskeletal stiffness, Nuchal rigidity, Parkinsonism
4Dystonia: Blepharospasm, Dystonia, Muscle tightness, Oromandibular dystonia, Torticollis, Trismus
5Other extrapyramidal diseases and abnormal movement disorders: Balance disorder, Bruxism, Drooling, Dysarthria, Gait deviation, Glabellar reflex abnormal, Hyporeflexia, Movement disorder, Restless legs syndrome, Salivary hypersecretion, Tongue movement disturbance
6Dyskinesia: Choreoathetosis, Dyskinesia, Grimacing, Oculogyric crisis, Protrusion tongue
Description of selected adverse reactions
Lens opacity/Cataract
Development of cataracts was observed in cariprazine non-clinical studies (see section 5.3). Therefore, cataract formation was closely monitored with slit lamp examinations in the clinical studies and patients with existing cataracts were excluded. During the schizophrenia clinical development program of cariprazine, few cataract cases were reported, characterized with minor lens opacities with no visual impairment (13/3192; 0.4%). Some of these patients had confounding factors. The most commonly reported ocular adverse event was blurred vision (placebo: 1/683; 0.1%, cariprazine: 22/2048; 1.1%).
Extrapyramidal symptoms (EPS)
In the short-term studies the incidence of EPS was observed in 27%; 11.5%; 30.7% and 15.1% in patients treated with cariprazine, placebo, risperidone and aripiprazole respectively. Akathisia was reported in 13.6%; 5.1%; 9.3% and 9.9% in patients treated with cariprazine, placebo, risperidone and aripiprazole respectively. Parkinsonism was experienced in 13.6%; 5.7%; 22.1% and 5.3% in patients treated with cariprazine, placebo, risperidone and aripiprazole respectively. Dystonia was observed in 1.8%; 0.2%; 3.6% and 0.7% in patients on cariprazine, placebo, risperidone and aripiprazole, respectively.
In the placebo-controlled part of the long-term maintenance of effect study EPS was 13.7% in the cariprazine group compared to 3.0% in the placebo treated patients. Akathisia was reported in 3.9% in patients treated with cariprazine, versus 2.0% in the placebo group. Parkinsonism was experienced in 7.8% and 1.0% in cariprazine and placebo group respectively.
In the negative symptom study EPS was reported in 14.3% in the cariprazine group and 11.7% in the risperidone treated patients. Akathisia was reported in 10.0% in patients treated with cariprazine and 5.2% in the risperidone group. Parkinsonism was experienced in 5.2% and 7.4% in cariprazine and risperidone treated patients respectively. Most EPS cases were mild to moderate in intensity and could be handled with common anti-EPS medicinal products. The rate of discontinuation due to EPS related ADRs was low.
Venous thromboembolism (VTE)
Cases of VTE, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotics - Frequency unknown.
Elevated liver transaminases
Elevated liver transaminases (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST]) are frequently observed with antipsychotic treatment. In the cariprazine clinical studies the incidence of ALT, AST elevation ADRs occurred in 2.2% of cariprazine-, 1.6% of risperidone- and 0.4% of placebo-treated patients. None of the cariprazine-treated patients had any liver damage.
Weight changes
In the short-term studies, there were slightly greater mean increases in body weight in the cariprazine group compared to the placebo group; 1 kg and 0.3 kg, respectively. In the long-term maintenance of effect study, there was no clinically relevant difference in change of body weight from baseline to end of treatment (1.1 kg for cariprazine and 0.9 kg for placebo). In the open-label phase of the study during 20 weeks cariprazine treatment 9.0% of patients developed potentially clinically significant (PCS) weight gain (defined as increase ≥ 7%) while during the double-blind phase, 9.8 % of the patients who continued with cariprazine treatment had PCS weight gain versus 7.1% of the patients who were randomized to placebo after the 20 week open-label cariprazine treatment. In the negative symptom study, the mean change of body weight was -0.3 kg for cariprazine and +0.6 kg for risperidone and PCS weight gain was observed in 6% of the cariprazine group while 7.4% of the risperidone group.
QT- prolongation
With cariprazine no QT interval prolongation was detected compared to placebo in a clinical study designed to assess QT prolongation (see section 5.1). In other clinical studies, only a few, non-serious, QT-prolongations have been reported with cariprazine. During the long-term, open-label treatment period in, 3 patients (0.4%) had QTcB > 500 msec, one of whom also had QTcF > 500 msec. A > 60 msec increase from baseline was observed in 7 patients (1%) for QTcB and in 2 patients (0.3%) for QTcF. In the long-term, maintenance of effect study, during the open-label phase, > 60 msec increase of from baseline was observed in 12 patients (1.6%) for QTcB and in 4 patients (0.5%) for QTcF. During the double-blind treatment period, > 60 msec increases from baseline in QTcB were observed in 3 cariprazine-treated patients (3.1%) and 2 placebo-treated patients (2%).
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 Ireland: HPRA Pharmacovigilance, website: www.hpra.ie, United Kingdom: Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Reagila 1.5 mg hard capsules | Clinical particulars - Overdose | Overdose
Symptoms
Accidental acute overdose (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day.
Management of overdose
Management of overdose should concentrate on supportive therapy including maintenance of an adequate airway, oxygenation and ventilation and management of symptoms. Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. In case of severe extrapyramidal symptoms, anticholinergic medicinal products should be administered. Since cariprazine is highly bound to plasma proteins, haemodialysis is unlikely to be useful in the management of overdose. Close medical supervision and monitoring should continue until the patient recovers.
There is no specific antidote to cariprazine.
5. Pharmacological properties
5.1 |
Reagila 1.5 mg hard capsules | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Cariprazine has two pharmacologically active metabolites with similar activities as cariprazine, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Total cariprazine (sum of cariprazine + DCAR and DDCAR) exposure approaches 50% of steady state exposure in ~1 week of daily dosing while 90% of steady state is achieved in 3 weeks. At steady state, exposure to DDCAR is approximately two to three-fold higher than to cariprazine, and exposure to DCAR is approximately 30% of cariprazine exposure.
Absorption
Absolute bioavailability of cariprazine is unknown. Cariprazine is well absorbed after oral administration. Following multiple-dose administration, peak plasma concentrations for cariprazine and the major active metabolites generally occur at approximately 3-8 hours post dose.
Administration of a single dose of 1.5 mg cariprazine with a high-fat meal (900 to 1,000 calories) did not significantly affect the Cmax or AUC of cariprazine (AUC0-∞ increased by 12%, Cmax decreased by < 5% under fed condition versus fasting). The effect of food on the exposure of the metabolites DCAR and DDCAR was also minimal.
Cariprazine can be administered with or without food.
Distribution
Based on a population pharmacokinetic analysis, the apparent volume of distribution (V/F) was 916 L for cariprazine, 475 L for DCAR and 1,568 L for DDCAR, indicating extensive distribution of cariprazine and its major active metabolites. Cariprazine and its major active metabolites are highly bound (96 to 97% for CAR, 94% to 97% for DCAR and 92% to 97% for DDCAR) to plasma proteins.
Biotransformation
The metabolism of cariprazine involves demethylation (DCAR and DDCAR), hydroxylation (hydroxy cariprazine, HCAR) and a combination of demethylation and hydroxylation (hydroxy desmethyl cariprazine, HDCAR and hydroxy didesmethyl cariprazine, HDDCAR). The metabolites of HCAR, HDCAR, and HDDCAR are subsequently biotransformed to their corresponding sulfate and glucuronide conjugates. An additional metabolite, desdichlorophenyl piperazine cariprazine (DDCPPCAR) acid, is produced by dealkylation and subsequent oxidation of cariprazine.
Cariprazine is metabolized by CYP3A4 and, to a lesser extent, by CYP2D6, to DCAR and HCAR. DCAR is further metabolized by CYP3A4 and to a lesser extent by CYP2D6 into DDCAR and HDCAR. DDCAR is further metabolised to HDDCAR by CYP3A4.
Cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), the organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), and the breast cancer resistance protein (BCRP). This suggests that an interaction of cariprazine with inhibitors of P-gp, OATP1B1, OATP1B3 and BCRP is unlikely.
Elimination
Elimination of cariprazine and its major active metabolites is mainly through hepatic metabolism. Following administration of 12.5 mg/day cariprazine to patients with schizophrenia, 20.8% of the dose was excreted in urine as cariprazine and its metabolites.
Unchanged cariprazine is excreted by 1.2% of the dose in urine and 3.7% of the dose in faeces.
The mean terminal half-life (1 to 3 days for cariprazine and DCAR and 13 to 19 days for DDCAR) is not predictive of time to reach steady state or plasma concentration decline after treatment discontinuation. For the management of patients treated with cariprazine, the effective half-life is more relevant than the terminal half-life. The effective (functional) half-life is ~ 2 days for cariprazine and DCAR, 8 days for DDCAR and is ~1 week for total cariprazine. The plasma concentration of total cariprazine will gradually decline following dose discontinuation or interruption. The plasma concentration of total cariprazine decreases by 50% in ~1 week and greater than 90% decline in total cariprazine concentration occurs in ~3 weeks.
Linearity
After repeated administration plasma exposure of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), increases proportionally over the therapeutic dose range of 1.5 to 6 mg.
Special populations
Renal impairment
Population pharmacokinetic modelling was performed using data from patients enrolled in the schizophrenia cariprazine clinical program with differing levels of renal function, including normal renal function (creatinine clearance (CrCl) ≥ 90 mL/min), as well as mild (CrCl 60 to 89 mL/min) and moderate (CrCl 30 to 59 mL/min) renal impairment. No significant relationship was found between cariprazine plasma clearance and creatinine clearance.
Cariprazine has not been evaluated in patients with severe (CrCl < 30 mL/min) renal impairment (see section 4.2).
Hepatic impairment
A 2-part study (a single dose of 1 mg cariprazine [Part A] and a daily dose of 0.5 mg cariprazine for 14 days [Part B] was conducted in patients with varying degrees of impaired hepatic function (Child-Pugh Classes A and B). Compared to healthy subjects, patients with either mild or moderate hepatic impairment had up to approximately 25% higher exposure (Cmax and AUC) for cariprazine and up to approximately 45% lower exposure for the major active metabolites, desmethyl cariprazine and didesmethyl cariprazine, following the single dose of 1 mg cariprazine or 0.5 mg cariprazine for 14 days.
The total active moiety (CAR+DCAR+DDCAR) exposure (AUC and Cmax) decreased by 21-22% and 13-15% in mild or moderate hepatic impairment (HI), respectively, compared to healthy subjects if unbound + bound concentrations were considered, while for unbound total moiety a decrease of 12-13% and an increase of 20-25% were calculated in mild HI patients and in moderate HI patients, respectively, after multiple dosing of cariprazine.
Cariprazine has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) (see section 4.2).
Age, gender and race
In the population PK analysis there were no clinically relevant differences in the PK parameters (AUC and Cmax of the sum of cariprazine and its major active metabolites) based on age, gender and race. This analysis included 2,844 patients of different races, involving 536 patients between the ages of 50 and 65. Of the 2,844 patients 933 were female (see section 4.2). In elderly patients above 65 years of age data are limited.
Smoking status
Because cariprazine is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of cariprazine.
Potential for cariprazine to affect other medicinal products
Cariprazine and its major active metabolites did not induce CYP1A2, CYP2B6 and CYP3A4 enzymes and were not inhibitors of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP219, CYP2D6, CYP2E1 and CYP3A4 in vitro. Cariprazine and its major active metabolites are not inhibitors of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro. DCAR and DDCAR were not inhibitors of transporter P-gp although cariprazine was a P-gp inhibitor in the intestine (see section 4.5).
5.3 |
Reagila 1.5 mg hard capsules | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Cariprazine caused bilateral cataract and secondary retinal changes (retinal detachment and cystic degeneration) in the dog. The exposure (AUC of total cariprazine) at the no-observed-adverse-effect-level (NOAEL) for ocular toxicity is 4.2-fold the clinical AUC exposure at the maximal recommended human dose (MRHD) of 6 mg/day. Increased incidence of retinal degeneration/atrophy was observed in albino rats in the 2-year study at clinically relevant exposures.
Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) and in the adrenal gland cortex of dogs at clinically relevant exposures. Inflammation was observed in the lungs of dogs dosed for 1 year with a NOAEL at AUC exposures 2.7 (males) and 1.7 (females) times the clinical exposure at the MRHD. No inflammation was observed at the end of 2-month drug-free period at an exposure 4.2 times the clinical exposure at the MRHD; however, inflammation was still present at higher doses.
Hypertrophy of the adrenal gland cortex was observed at 4.1 times the clinical exposure at the MRHD in rats (females only) and at clinically relevant total cariprazine plasma concentrations in mice. In dogs, reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortex were observed with a NOAEL 4.2 times the clinical exposure at the MRHD.
In female rats, lower fertility and conception indices were observed at clinically relevant exposures based on mg/m2 body surface area. No effects on male fertility were noted at exposures up to 4.3 times the clinical exposure at the MRHD.
Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the MRHD of 6 mg/day. In rabbits, cariprazine caused maternal toxicity, but no foetal toxicity at exposures 5.8 times the clinical exposure at the MRHD.
Administration of cariprazine to pregnant rats during the period of organogenesis, throughout pregnancy and lactation at clinically relevant exposures decreased postnatal survival, birth weight, and post-weaning body weight of first-generation pups. In addition, pale, cold bodies and developmental delays (renal papillae not developed/underdeveloped and decreased auditory startle response in males) were observed in the absence of maternal toxicity. Reproductive performance of the first-generation pups was unaffected; however, second generation pups also had similar clinical signs and lower body weight.
Cariprazine and its metabolites were excreted in milk of rats during lactation.
6. |
Reagila 1.5 mg hard capsules | Pharmaceutical particulars - List of excipients | List of excipients
Capsule contents
Pregelatinized (maize) starch
Magnesium stearate
Capsule shell (1.5 mg capsule)
Titanium dioxide (E 171)
Gelatin
Capsule shell (3 mg capsule)
Allura red AC (E 129)
Brilliant blue FCF (E 133)
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Gelatin
Capsule shell (4.5 mg capsule)
Allura red AC (E 129)
Brilliant blue FCF (E 133)
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Gelatin
Capsule shell (6 mg capsule)
Brilliant blue FCF (E 133)
Allura red AC (E 129)
Titanium dioxide (E 171)
Gelatin
Printing ink (black: 1.5 mg, 3 mg and 6 mg capsules)
Shellac
Black iron oxide (E 172)
Propylene glycol
Potassium hydroxide
Printing ink (white: 4.5 mg capsule)
Shellac
Titanium dioxide (E 171)
Propylene glycol
Simeticone
6.2 |
Reagila 1.5 mg hard capsules | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Reagila 1.5 mg hard capsules | Pharmaceutical particulars - Shelf life | Shelf life
5 years
6.4 |
Reagila 1.5 mg hard capsules | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Keep the blister in the outer carton in order to protect from light.
This medicinal product does not require any special temperature storage conditions.
6.5 |
Reagila 1.5 mg hard capsules | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Transparent hard PVC/PE/PVDC blister heat-sealed with hard aluminium foil backing packed in folded carton box.
Reagila 1.5 mg and Reagila 3 mg hard capsules
Cartons contain 7, 14, 21, 28, 30, 49, 56, 60, 84, 90 or 98 hard capsules.
Reagila 4.5 mg and Reagila 6 mg hard capsules
Cartons contain 7, 21, 28, 30, 49, 56, 60, 84, 90 or 98 hard capsules.
Not all pack sizes may be marketed.
6.6 |
Reagila 1.5 mg hard capsules | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
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