medication_name stringlengths 6 170 | section_title stringclasses 42 values | text stringlengths 0 47.1k |
|---|---|---|
Glycerol 2g Suppositories | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
The product is intended for occasional use only. Prolonged or excessive use of the product is not recommended as this may cause diarrhoea. Use of this product may interfere with glucose control in diabetic patients. If symptoms persist consult a doctor.
4.5 |
Glycerol 2g Suppositories | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed
4.6 Pregnancy and lactation
No evidence of harmful affects available. However, best avoided during the first trimester of pregnancy. May be used during breast feeding.
4.7 |
Glycerol 2g Suppositories | Clinical particulars - Fertility, pregnancy and lactation | Effects on ability to drive and use machines
None stated.
4.8 |
Glycerol 2g Suppositories | Clinical particulars - Effects on ability to drive and use machines | Undesirable effects
Use of the product may occasionally cause abdominal cramps. Glycerol can cause irritation when given rectally.
4.9 |
Glycerol 2g Suppositories | Clinical particulars - Undesirable effects | Overdose
Overdosage via rectal route is unlikely. However, if ingested treat symptomatically.
5. Pharmacological properties
5.1 |
Glycerol 2g Suppositories | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Glycerol following rectal administration is poorly absorbed.
5.3 |
Glycerol 2g Suppositories | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
There are no preclinical data of relevance to the prescriber, which are additional to those already included in other sections of the SmPC
6. |
Glycerol 2g Suppositories | Pharmaceutical particulars - List of excipients | List of excipients
Gelatin Purified Water
6.2 |
Glycerol 2g Suppositories | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable
6.3 |
Glycerol 2g Suppositories | Pharmaceutical particulars - Shelf life | Shelf life
3 years
6.4 |
Glycerol 2g Suppositories | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store below 25°C in a dry place
6.5 |
Glycerol 2g Suppositories | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Heat sealed cavities composed of Polyvinyl Chloride (PVC) coated with Polyvinylidene Chloride (PVDC) and laminated with polyethylene (PE), each containing 1x 4g suppository in strips of 6. The strips and a patient leaflet are packed into cardboard cartons. Pack size available: 12 x 4g.
6.6 |
Glycerol 2g Suppositories | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Wash hands before opening individual packaging. The suppository is shaped for rectal insertion, ensure the tip of the suppository is inserted first. The tip should be moistened with a little cold water to aid insertion.
7. |
Glycerol 2g Suppositories | Marketing authorisation holder | Martindale Pharmaceuticals Ltd.Bampton Road, Romford, RM3 8UGUnited Kingdom
8. Marketing authorisation number(s)
PL 00156/0120
9. |
Glycerol 2g Suppositories | Date of first authorisation/renewal of the authorisation | 13/07/2009
10. |
Glycerol 2g Suppositories | Date of revision of the text | 02/10/2013 |
Glycerol 4g Suppositories | Name of the medicinal product | Glycerol 4g Suppositories
2. |
Glycerol 4g Suppositories | Qualitative and quantitative composition | Each suppository contains 2800mg GlycerolFor full list of excipients , see 6.1.
3. |
Glycerol 4g Suppositories | Pharmaceutical form | Amber coloured suppository, of nominal weight 4g intended for rectal administration.
4. |
Glycerol 4g Suppositories | Clinical particulars - Therapeutic indications | Therapeutic indications
For occasional use as a stimulant laxative for the treatment of constipation.
4.2 |
Glycerol 4g Suppositories | Clinical particulars - Posology and method of administration | Posology and method of administration
For rectal use.
Adults and the elderly
One 4g suppository, to aid insertion the suppository tip should be moistened with water before use. No reduction in adult dosage is necessary for elderly patients.
Infants and Children
Not recommended
4.3 |
Glycerol 4g Suppositories | Clinical particulars - Contraindications | Contraindications
• Hypersensitivity to the active substance or to any of the excipients. • The product is contraindicated if there is intestinal obstruction or blockage.
4.4 |
Glycerol 4g Suppositories | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
The product is intended for occasional use only. Prolonged or excessive use of the product is not recommended as this may cause diarrhoea. Use of this product may interfere with glucose control in diabetic patients. If symptoms persist consult a doctor.
4.5 |
Glycerol 4g Suppositories | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
None stated.
4.6. Pregnancy and lactation
No evidence of harmful affects available. However, best avoided during the first trimester of pregnancy. May be used during breast feeding.
4.7 |
Glycerol 4g Suppositories | Clinical particulars - Fertility, pregnancy and lactation | Effects on ability to drive and use machines
None stated
4.8 |
Glycerol 4g Suppositories | Clinical particulars - Effects on ability to drive and use machines | Undesirable effects
Use of the product may occasionally cause abdominal cramps. Glycerol can cause irritation when given rectally.
4.9 |
Glycerol 4g Suppositories | Clinical particulars - Undesirable effects | Overdose
Overdosage via rectal route is unlikely. However, if ingested treat symptomatically.
5. Pharmacological properties
5.1 |
Glycerol 4g Suppositories | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Glycerol following rectal administration is poorly absorbed.
5.3 |
Glycerol 4g Suppositories | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
No additional pre-clinical data of relevance to the prescriber.
6. |
Glycerol 4g Suppositories | Pharmaceutical particulars - List of excipients | List of excipients
Gelatin Purified Water
6.2 |
Glycerol 4g Suppositories | Pharmaceutical particulars - Incompatibilities | Incompatibilities
None stated
6.3 |
Glycerol 4g Suppositories | Pharmaceutical particulars - Shelf life | Shelf life
3 years (36 Months)
6.4 |
Glycerol 4g Suppositories | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store below 25°C in a dry place
6.5 |
Glycerol 4g Suppositories | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Heat sealed cavities composed of Polyvinyl Chloride (PVC) coated with Polyvinylidene Chloride (PVDC) and laminated with polyethylene (PE), each containing 1x 4g suppository in strips of 6. The strips and a patient leaflet are packed into cardboard cartons. Pack size available: 12 x 4g.
6.6 |
Glycerol 4g Suppositories | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Wash hands before opening individual packaging. The suppository is shaped for rectal insertion, ensure the tip of the suppository is inserted first. The tip should be moistened with a little cold water to aid insertion.
7. |
Glycerol 4g Suppositories | Marketing authorisation holder | Martindale Pharmaceuticals LtdBampton RoadRomfordRM3 8UG
8. Marketing authorisation number(s)
PL 00156/0053
9. |
Glycerol 4g Suppositories | Date of first authorisation/renewal of the authorisation | 18/05/2004
10. |
Glycerol 4g Suppositories | Date of revision of the text | 02/10/2013 |
Rasagiline Brown and Burk 1mg Tablets | Name of the medicinal product | Rasagiline Brown & Burk 1mg Tablets
2. |
Rasagiline Brown and Burk 1mg Tablets | Qualitative and quantitative composition | Each tablet contains 1 mg Rasagiline (as tartrate).
For the full list of excipients, see section 6.1.
3. |
Rasagiline Brown and Burk 1mg Tablets | Pharmaceutical form | Tablet
White to off-white, circular, flat faced bevelled edge, uncoated tablets, with “1” debossed on one face and plain on other face.
4. |
Rasagiline Brown and Burk 1mg Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Rasagiline Brown & Burk is indicated in adults for the treatment of idiopathic Parkinson's disease as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations.
4.2 |
Rasagiline Brown and Burk 1mg Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology:
The recommended dose of rasagiline is 1 mg (one tablet of Rasagiline Brown & Burk ) once daily to be taken with or without levodopa.
Elderly:
No change in dose is required for elderly patients (see section 5.2).
Hepatic impairment:
Rasagiline is contraindicated in patients with severe hepatic impairment (see section 4.3). Rasagiline use in patients with moderate hepatic impairment should be avoided. Caution should be used when initiating treatment with rasagiline in patients with mild hepatic impairment. In case patients progress from mild to moderate hepatic impairment rasagiline should be stopped (see section 4.4 and 5.2).
Renal impairment:
No special precautions are required in patients with renal impairment.
Paediatric population:
The safety and efficacy of Rasagiline Brown & Burk in children and adolescents have not been established. There is no relevant use of Rasagiline Brown & Burk in the paediatric population in the indication Parkinson's disease.
Method of administration
For oral use.
Rasagiline may be taken with or without food.
4.3 |
Rasagiline Brown and Burk 1mg Tablets | 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 and initiation of treatment with MAO inhibitors or pethidine.
Severe hepatic impairment.
4.4 |
Rasagiline Brown and Burk 1mg Tablets | 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 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. At least 14 days should elapse between discontinuation of rasagiline 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 reactions of levodopa may be increased and pre-existing dyskinesia exacerbated. Decreasing the dose of levodopa may ameliorate this adverse reaction.
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 reactions 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)
ICD 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 behavioural 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 inpatients 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 in patients with mild hepatic impairment. Rasagiline use in patients with moderate hepatic impairment should be avoided. In case patients progress from mild to moderate hepatic impairment, rasagiline should be stopped (see section 5.2).
4.5 |
Rasagiline Brown and Burk 1mg Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
MAO Inhibitors
Rasagiline is contraindicated 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).
Pethidine
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 and pethidine is contraindicated (see section 4.3).
Sympathomimetics
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 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).
Dextromethorphan
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 and dextromethorphan is not recommended (see section 4.4).
SNRI/SSRI/tri- and tetracyclic antidepressants
The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided (see section 4.4).
For concomitant use of rasagiline 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.
Agents that affect CYP1A2 activity
In vitro metabolism studies have indicated that cytochrome P450 1A2 (CYP1A2) is the major enzyme responsible for the metabolism of rasagiline.
CYP1A2 inhibitors
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.
CYP1A2 inducers
There is a risk that the plasma levels of rasagiline in smoking patients could be decreased, due to induction of the metabolising enzyme CYP1A2.
Other cytochrome P450 isoenzymes
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 (see section 5.3).
Levodopa and other Parkinson's disease medicinal products
In Parkinson's disease patients receiving rasagiline as adjunct therapy to chronic levodopa treatment, there was no clinically significant effect of levodopa treatment on rasagiline clearance.
Concomitant administration of rasagiline and entacapone increased rasagiline oral clearance by 28%.
Tyramine/rasagiline interaction:
Results of five tyramine challenge studies (in volunteers and Parkinson's disease 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 can be used safely without dietary tyramine restrictions.
4.6 |
Rasagiline Brown and Burk 1mg Tablets | 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 Brown and Burk 1mg Tablets | 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 Brown and Burk 1mg Tablets | 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 listed below in Tables 1 and 2 by system organ class and 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), not known (cannot be estimated from the available data).
Monotherapy
The tabulated 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
Adjunct Therapy
The tabulated 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Rasagiline Brown and Burk 1mg Tablets | Clinical particulars - Overdose | Overdose
Symptoms
Symptoms reported following overdose of rasagiline in doses ranging from 3 mg to 100 mg included, hypomania, hypertensive crisis and serotonin syndrome. |
Rasagiline Brown and Burk 1mg Tablets | 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 reactions 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 adverse reactions (including hypertension and postural hypotension) which resolved following treatment discontinuation. These symptoms may resemble those observed with non-selective MAO inhibitors.
Management
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 Brown and Burk 1mg Tablets | 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. Ex vivo and in vitro experiments demonstrate that rasagiline is neither inhibitor nor inducer of major CYP450 enzymes (see section 4.5).
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 is linear with dose over the range of 0.5-2 mg in Parkinson's disease patients. Its terminal half-life is 0.6-2 hours.
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).
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.
Elderly
Age has little influence on rasagiline pharmacokinetics in the elderly (> 65 years) (see section 4.2)
5.3 |
Rasagiline Brown and Burk 1mg Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazard for humans based on the standard studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity, 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 Brown and Burk 1mg Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Microcrystalline cellulose
Maize starch 5%
Pregelatinised starch
Citric acid monohydrate
Colloidal silicon dioxide
Stearic acid
Talc
6.2 |
Rasagiline Brown and Burk 1mg Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable
6.3 |
Rasagiline Brown and Burk 1mg Tablets | Pharmaceutical particulars - Shelf life | Shelf life
36 months
6.4 |
Rasagiline Brown and Burk 1mg Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C.
6.5 |
Rasagiline Brown and Burk 1mg Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
OPA/Al/PVC/Al blister packs of 7, 10, 14, 28, 30, 100 and 112 tablets.
PVC/ACLAR/Al blister packs of 7, 10, 14, 28, 30, 100 and 112 tablets.
Not all pack sizes may be marketed.
6.6 |
Rasagiline Brown and Burk 1mg 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. |
Rasagiline Brown and Burk 1mg Tablets | Marketing authorisation holder | Brown & Burk UK Limited,
5 Marryat Close,
Hounslow,
TW4 5DQ,
United Kingdom
8. Marketing authorisation number(s)
PL 25298/0097
9. |
Rasagiline Brown and Burk 1mg Tablets | Date of first authorisation/renewal of the authorisation | 13/11/2017
10. |
Rasagiline Brown and Burk 1mg Tablets | Date of revision of the text | 12/07/2021 |
Rasagiline Dr. Reddy's 1mg Tablets | Name of the medicinal product | Rasagiline Dr. Reddy's 1 mg Tablets
2. |
Rasagiline Dr. Reddy's 1mg Tablets | Qualitative and quantitative composition | Each tablet contains 1 mg rasagiline (as hemitartrate).
For the full list of excipients, see section 6.1.
3. |
Rasagiline Dr. Reddy's 1mg Tablets | Pharmaceutical form | Tablets
White to off-white, round, flat bevel edged, 8 mm tablets, debossed with 'R' on one side and '1' on the other side.
4. |
Rasagiline Dr. Reddy's 1mg Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Rasagiline is indicated in adults for the treatment of idiopathic Parkinson's disease as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations.
4.2 |
Rasagiline Dr. Reddy's 1mg Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The recommended dose of rasagiline is 1 mg (one tablet) once daily, to be taken with or without levodopa.
Elderly
No change in dose is required for elderly patients (see section 5.2).
Hepatic impairment
Rasagiline is contraindicated in patients with severe hepatic impairment (see section 4.3). Rasagiline use in patients with moderate hepatic impairment should be avoided. Caution should be used when initiating treatment with rasagiline in patients with mild hepatic impairment. In case patients progress from mild to moderate hepatic impairment rasagiline should be stopped (see section 4.4 and 5.2).
Renal impairment
No special precautions are required in patients with renal impairment.
Paediatric population
The safety and efficacy of rasagiline in children and adolescents have not been established. There is no relevant use of rasagiline in the paediatric population in the indication Parkinson's disease.
Method of administration
For oral use.
Rasagiline may be taken with or without food.
4.3 |
Rasagiline Dr. Reddy's 1mg Tablets | 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 and initiation of treatment with MAO inhibitors or pethidine.
Severe hepatic impairment.
4.4 |
Rasagiline Dr. Reddy's 1mg Tablets | 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 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. At least 14 days should elapse between discontinuation of rasagiline 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 reactions of levodopa may be increased and pre-existing dyskinesia exacerbated. Decreasing the dose of levodopa may ameliorate this adverse reaction.
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 reactions 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)
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 behavioural 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.
Serotonin syndrome
Concomitant administration of serotonergic agents, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants and buprenorphine-containing medicinal products, may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).
If concomitant treatment with buprenorphine-containing medicinal products is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.
If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.
Hepatic impairment
Caution should be used when initiating treatment with rasagiline in patients with mild hepatic impairment. Rasagiline use in patients with moderate hepatic impairment should be avoided. In case patients progress from mild to moderate hepatic impairment, rasagiline should be stopped (see section 5.2).
4.5 |
Rasagiline Dr. Reddy's 1mg Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
MAO Inhibitors
Rasagiline is contraindicated 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).
Buprenorphine-containing medicinal products
Rasagiline should be used cautiously when co-administered with buprenorphine-containing medical products as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).
Pethidine
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 and pethidine is contraindicated (see section 4.3).
Sympathomimetics
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 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).
Dextromethorphan
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 and dextromethorphan is not recommended (see section 4.4).
SNRI/SSRI/tri- and tetracyclic antidepressants
The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided (see section 4.4).
For concomitant use of rasagiline 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.
Agents that affect CYP1A2 activity
In vitro metabolism studies have indicated that cytochrome P450 1A2 (CYP1A2) is the major enzyme responsible for the metabolism of rasagiline.
CYP1A2 inhibitors
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.
CYP1A2 inducers
There is a risk that the plasma levels of rasagiline in smoking patients could be decreased, due to induction of the metabolising enzyme CYP1A2.
Other cytochrome P450 isoenzymes
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 (see section 5.3).
Levodopa and other Parkinson's disease medicinal products
In Parkinson's disease patients receiving rasagiline as adjunct therapy to chronic levodopa treatment, there was no clinically significant effect of levodopa treatment on rasagiline clearance.
Concomitant administration of rasagiline and entacapone increased rasagiline oral clearance by 28%.
Tyramine/rasagiline interaction
Results of five tyramine challenge studies (in volunteers and Parkinson's disease 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 can be used safely without dietary tyramine restrictions.
4.6 |
Rasagiline Dr. Reddy's 1mg Tablets | 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 Dr. Reddy's 1mg Tablets | 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 Dr. Reddy's 1mg Tablets | 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 listed below in Tables 1 and 2 by system organ class and 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), not known (cannot be estimated from the available data).
Monotherapy
The tabulated 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
Adjunct Therapy
The tabulated 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 (including cysts and polyps)
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, pethidine, tramadol, buprenorphine, 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, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Rasagiline Dr. Reddy's 1mg Tablets | Clinical particulars - Overdose | Overdose
Symptoms: Symptoms reported following overdose of rasagiline in doses ranging from 3 mg to 100 mg included hypomania, hypertensive crisis and serotonin syndrome. |
Rasagiline Dr. Reddy's 1mg Tablets | 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 reactions 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 adverse reactions (including hypertension and postural hypotension) which resolved following treatment discontinuation. These symptoms may resemble those observed with non-selective MAO inhibitors.
Management
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 Dr. Reddy's 1mg Tablets | 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. Ex vivo and in vitro experiments demonstrate that rasagiline is neither inhibitor nor inducer of major CYP450 enzymes (see section 4.5).
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 is linear with dose over the range of 0.5-2 mg in Parkinson's disease patients. Its terminal half-life is 0.6-2 hours.
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).
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.
Elderly
Age has little influence on rasagiline pharmacokinetics in the elderly (> 65 years) (see section 4.2).
5.3 |
Rasagiline Dr. Reddy's 1mg Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazard for humans based on the standard studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, 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 Dr. Reddy's 1mg Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Microcrystalline cellulose
Starch, pre-gelatinised (from maize starch)
Maize starch
Talc
Stearic acid
6.2 |
Rasagiline Dr. Reddy's 1mg Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Rasagiline Dr. Reddy's 1mg Tablets | Pharmaceutical particulars - Shelf life | Shelf life
2 years
6.4 |
Rasagiline Dr. Reddy's 1mg Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Rasagiline Dr. Reddy's 1mg Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Alu-Alu (OPA/Alu/PVC-Alu) blister packs.
Pack sizes: 28, 30, 60, 100 tablets
Not all pack sizes may be marketed.
6.6 |
Rasagiline Dr. Reddy's 1mg 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. |
Rasagiline Dr. Reddy's 1mg Tablets | Marketing authorisation holder | Dr. Reddy's Laboratories (UK) Ltd.
6 Riverview Road
Beverley
East Yorkshire
HU17 0LD
United Kingdom
8. Marketing authorisation number(s)
PL 08553/0549
9. |
Rasagiline Dr. Reddy's 1mg Tablets | Date of first authorisation/renewal of the authorisation | 02/03/2016
10. |
Rasagiline Dr. Reddy's 1mg Tablets | Date of revision of the text | 29/04/2022 |
Rasagiline Milpharm 1 mg tablets | Name of the medicinal product | Rasagiline Milpharm 1 mg tablets
2. |
Rasagiline Milpharm 1 mg tablets | Qualitative and quantitative composition | Each tablet contains 1 mg rasagiline (as tartrate).
For the full list of excipients, see section 6.1.
3. |
Rasagiline Milpharm 1 mg tablets | Pharmaceutical form | Tablet.
White to off-white, oblong (approximately 11.5 mm x 6 mm), biconvex tablets, debossed with 'R9SE' on one side and '1' on the other side.
4. |
Rasagiline Milpharm 1 mg tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Rasagiline is indicated in adults for the treatment of idiopathic Parkinson's disease as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations.
4.2 |
Rasagiline Milpharm 1 mg tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The recommended dose of rasagiline is 1 mg (one tablet of Rasagiline) once daily, to be taken with or without levodopa.
Elderly
No change in dose is required for elderly patients (see section 5.2).
Hepatic impairment
Rasagiline is contraindicated in patients with severe hepatic impairment (see section 4.3). Rasagiline use in patients with moderate hepatic impairment should be avoided. Caution should be used when initiating treatment with rasagiline in patients with mild hepatic impairment. In case patients progress from mild to moderate hepatic impairment rasagiline should be stopped (see section 4.4 and 5.2).
Renal impairment
No special precautions are required in patients with renal impairment.
Paediatric population
The safety and efficacy of rasagiline in children and adolescents have not been established. There is no relevant use of Rasagiline in the paediatric population in the indication Parkinson's disease.
Method of administration
For oral use.
Rasagiline may be taken with or without food.
4.3 |
Rasagiline Milpharm 1 mg tablets | 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 and initiation of treatment with MAO inhibitors or pethidine.
Severe hepatic impairment.
4.4 |
Rasagiline Milpharm 1 mg tablets | 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 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. At least 14 days should elapse between discontinuation of rasagiline 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 reactions of levodopa may be increased and pre-existing dyskinesia exacerbated. Decreasing the dose of levodopa may ameliorate this adverse reaction.
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 reactions 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)
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 behavioural 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 in patients with mild hepatic impairment. Rasagiline use in patients with moderate hepatic impairment should be avoided. In case patients progress from mild to moderate hepatic impairment, rasagiline should be stopped (see section 5.2).
Serotonin syndrome
Concomitant administration of serotonergic agents, such as selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants, and buprenorphine-containing medicinal products may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).
If concomitant treatment with buprenorphine-containing medicinal products is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.
4.5 |
Rasagiline Milpharm 1 mg tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
MAO Inhibitors
Rasagiline is contraindicated 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).
Buprenorphine-containing medicinal products
Rasagiline should be used cautiously when co-administered with Buprenorphine-containing medical products as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).
Pethidine
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 and pethidine is contraindicated (see section 4.3).
Sympathomimetics
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 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).
Dextromethorphan
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 and dextromethorphan is not recommended (see section 4.4).
SNRI/SSRI/tri- and tetracyclic antidepressants
The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided (see section 4.4).
For concomitant use of rasagiline 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 as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4). Therefore, in view of the MAO inhibitory activity of rasagiline, antidepressants should be administered with caution.
Agents that affect CYP1A2 activity
In vitro metabolism studies have indicated that cytochrome P450 1A2 (CYP1A2) is the major enzyme responsible for the metabolism of rasagiline.
CYP1A2 inhibitors
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.
CYP1A2 inducers
There is a risk that the plasma levels of rasagiline in smoking patients could be decreased, due to induction of the metabolising enzyme CYP1A2.
Other cytochrome P450 isoenzymes
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 (see section 5.3).
Levodopa and other Parkinson's disease medicinal products
In Parkinson's disease patients receiving rasagiline as adjunct therapy to chronic levodopa treatment, there was no clinically significant effect of levodopa treatment on rasagiline clearance.
Concomitant administration of rasagiline and entacapone increased rasagiline oral clearance by 28%.
Tyramine/rasagiline interaction
Results of five tyramine challenge studies (in volunteers and Parkinson's disease 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 can be used safely without dietary tyramine restrictions.
4.6 |
Rasagiline Milpharm 1 mg tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of rasagiline in pregnant women. Animals 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.
Breastfeeding
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 Milpharm 1 mg tablets | 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 Milpharm 1 mg tablets | 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 listed below in Tables 1 and 2 by system organ class and 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) ), not known (cannot be estimated from the available data).
Monotherapy
The tabulated 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
Adjunct Therapy
The tabulated 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 (incl cysts and polyps)
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
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
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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Rasagiline Milpharm 1 mg tablets | Clinical particulars - Overdose | Overdose
Symptoms
Symptoms reported following overdose of rasagiline in doses ranging from 3 mg to 100 mg included, hypomania, hypertensive crisis and serotonin syndrome. |
Rasagiline Milpharm 1 mg tablets | 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 reactions 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 adverse reactions (including hypertension and postural hypotension) which resolved following treatment discontinuation. These symptoms may resemble those observed with non-selective MAO inhibitors.
Management
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 Milpharm 1 mg tablets | 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. Ex vivo and in vitro experiments demonstrate that rasagiline is neither inhibitor nor inducer of major CYP450 enzymes (see section 4.5).
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 is linear with dose over the range of 0.5-2 mg in Parkinson's disease patients. Its terminal half-life is 0.6-2 hours.
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).
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.
Elderly
Age has little influence on rasagiline pharmacokinetics in the elderly (> 65 years) (see section 4.2)
5.3 |
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