Summary Basis of Decision for Invega
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Invega
Paliperidone, 3 mg, 6 mg, 9 mg, 12 mg, extended-release tablets, oral
Janssen-Ortho Inc.
Submission control no: 108748
Date issued: 2008-04-29
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrINVEGA, Palipéridone, 3 mg, 6 mg, 9 mg, 12 mg, Janssen-Ortho Inc.,
No de contrôle de la présentation 108748
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02300273 - 3 mg
- 02300281 - 6 mg
- 02300303 - 9 mg
- 02300311 - 12 mg
Therapeutic Classification:
Non-medicinal ingredients:
The 3 mg tablets also contain lactose and triacetin.
Submission type and control no:
Control No. 108748
Date of Submission:
Date of authorization:
* All trademark rights used under license
2 Notice of decision
On September 26, 2007, Health Canada issued a Notice of Compliance to Janssen-Ortho Inc. for the drug product Invega.
Invega contains the medicinal ingredient paliperidone which is the major metabolite of RISPERDAL* (risperidone), an atypical antipsychotic which is approved for the treatment of schizophrenia since April 1993. Paliperidone shares the characteristic serotonin (5HT2A) and dopamine (D2) antagonism and receptor binding profile of its parent risperidone. Paliperidone is not metabolized to any significant extent by cytochrome P-450 isozymes, and therefore is not expected to interact with drugs metabolized by these isozymes. Paliperidone is presented as an extended-release formulation which uses the OROS* delivery system.
Invega is indicated for the treatment of schizophrenia. In controlled clinical trials, Invega was found to improve the symptoms of schizophrenia, including positive and negative symptoms. The mechanism of action of paliperidone is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5-HT2A) receptor antagonism.
The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy of Invega were evaluated in three placebo-controlled, double-blind, 6-week studies in non-elderly patients (n=1665, mean age 37 years) with schizophrenia. The primary efficacy endpoint was evaluated using the Positive and Negative Syndrome Scale (PANSS). In all three studies, Invega was superior to placebo on the PANSS.
Invega (3 mg, 6 mg, 9 mg, and 12 mg, paliperidone) is presented as extended-release tablets. The recommended starting and target dose of Invega is 6 mg once daily. No initial dose titration is required. However, in some cases a lower dose of 3 mg/day may be sufficient. Dosing guidelines are available in the Product Monograph.
Invega is contraindicated for patients who are hypersensitive to paliperidone, risperidone, or to any ingredient in the formulation or component of the container. Detailed conditions for the use of Invega are described in the Product Monograph.Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Invega is favourable for the treatment of schizophrenia.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Paliperidone, the medicinal ingredient of Invega, is an antipsychotic agent indicated for the treatment of schizophrenia. The mechanism of action of paliperidone is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5-HT2A) receptor antagonism.
Manufacturing Process and Process Controls
The drug substance is synthetically derived.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The chemical structure of paliperidone contains a chiral center and is manufactured as a racemic mixture. The structure of paliperidone was adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered adequately qualified
(i.e. within ICH limits and/or qualified from toxicological studies) and therefore, are considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of paliperidone.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Invega extended-release tablets are capsule-shaped. Orifices may or may not be visible. The tablets are presented in four dosage strengths:
- 3 mg - A white tablet printed with "PAL 3".
- 6 mg - A beige tablet printed with "PAL 6".
- 9 mg - A pink tablet printed with "PAL 9".
- 12 mg - A dark-yellow tablet printed with "PAL 12".
Each dosage strength is packaged in bottles of 30 and 350 tablets, as well as blisters of 30 tablets.
Invega tablets contain paliperidone as the medicinal ingredient. The following non-medicinal ingredients are common to all tablet strengths: butylated hydroxytoluene, carnauba wax, cellulose acetate, ferric oxide red, ferric oxide yellow, hydroxyethyl cellulose, hypromellose, iron oxide black, polyethylene oxides, polyethylene glycol, propylene glycol, povidone, sodium chloride, stearic acid, and titanium dioxide. The 3 mg tablets also contain lactose monohydrate and triacetin.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of paliperidone with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Invega is tested to verify that the identity, appearance, content uniformity, levels of degradation products and impurities, release rate, residual solvent, and water content are within acceptance criteria. The test specifications are considered acceptable.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, the proposed limits are considered adequately qualified i.e. within ICH limits and/or qualified from toxicological studies.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Invega.
No deficiencies were found with respect to the container closure system.
Stability
Based on the long-term and accelerated stability data submitted, the proposed 24-month shelf-life at 15-30°C for Invega is considered acceptable, when stored in its original package.
3.1.3 Facilities and Equipment
The facilities and equipment involved in the production of Invega are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Invega has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
The medicinal ingredient of Invega, paliperidone (9-hydroxy-risperidone), is the major metabolite of risperidone which is a widely used atypical antipsychotic approved for the treatment of schizophrenia and other psychiatric disorders. Paliperidone and risperidone have similar pharmacological profiles. Paliperidone is a receptor monoaminergic antagonist that exhibits the characteristic dopamine Type 2 (D2) and serotonin (5-hydroxytryptamine [5-HT] Type 2A [5-HT2A]) antagonism of antipsychotic drugs. Most of the non-clinical pharmacology and the absorption, distribution, metabolism and excretion (ADME) studies on paliperidone were performed at the time when studies were conducted to support the marketing application of risperidone. Some of the repeat-dose toxicity studies for paliperidone also included risperidone.
3.2.1 Pharmacodynamics
Paliperidone displayed high affinity for 5-HT2A and D2 receptors, and was also active as an antagonist at the α1-and α2-adrenergic receptors and the H1-receptor. Binding affinities and profiles for all investigated receptor sites were similar for paliperidone, its enantiomers, and risperidone. Several in vivo studies were performed in rats and dogs. Overall, paliperidone induced the expected effects, and the investigated in vivo effects were qualitatively and quantitatively similar for paliperidone and risperidone. Secondary pharmacodynamic effects and the non-clinical side-effect profile of paliperidone were very similar to those of risperidone. Anti-adrenergic and anti-histaminergic effects are suspected to elicit hypotensive and sedative effects. Hyperprolactinemia was expected due to the D2-receptor antagonism.
Markers for torsadogenic potential were seen in in vitro studies with concentrations of =1µM paliperidone. When these concentrations were compared to therapeutically effective free plasma concentrations, paliperidone seems to have a low torsadogenic potential. Nevertheless, since Torsade de pointes may occur with antipsychotics, the torsadogenic potential of paliperidone has been included in the Product Monograph. In vivo studies performed in guinea pigs and dogs with paliperidone doses yielding plasma concentrations slightly in excess of the therapeutic ones in humans did not show marked effects on QTc.
The pharmacological profiles of paliperidone and the two paliperidone enantiomers are comparable both in vitro and in vivo and also closely resemble that of risperidone.
3.2.2 Pharmacokinetics
Absorption
Paliperidone was well absorbed in dogs and rats after oral administration of a paliperidone solution. The absolute bioavailability was estimated at 94.4% in dogs, 78% in female rats and 46% in male rats. The gender difference observed in the rat species is consistent with the higher rate of metabolism in male rats.
Distribution
Paliperidone was rapidly and widely distributed in rats and dogs. In rats, the highest concentrations were found in liver, small intestinal tissue, and salivary gland. The lowest concentrations were measured in brain, muscle, white fat, and testis. In dogs, the highest tissue concentrations were seen in the liver, lung, and kidney. Paliperidone did cross the blood-brain barrier. No study on placental transfer was performed with paliperidone but available data for risperidone in rats indicate that placental transfer was limited. In rats, paliperidone and/or its metabolites were excreted into milk.
In the plasma protein binding studies, paliperidone was bound to a maximum of 85% in all species tested.
Metabolism
In rats, paliperidone was extensively metabolized and the excretion of unchanged paliperidone accounted for 3.19% and 6.42% of the dose for males and females, respectively. In rat plasma, unchanged paliperidone was the major compound (50-68%) observed. In rats, paliperidone was mostly metabolized by alicyclic hydroxylation, oxidative N-dealkylation and benzisoxazole scission.
In dogs, metabolism was limited and after 48 hours the unchanged paliperidone accounted for 32.4% of the dose in the urine and 0% in the feces. Unchanged paliperidone accounted for 82% of the total paliperidone-related radioactivity in plasma. The metabolic pathways were similar to the rats. The biotransformation products resulted from oxidative N-dealkylation, alcohol dehydrogenation and benzisoxazole scission, with or without glucuronidation, alicyclic mono-hydroxylation or di-hydroxylation.
The metabolites observed following administration of paliperidone were also observed following risperidone administration. Thus, no new metabolites were identified after the oral administration of paliperidone compared to risperidone.
Excretion
In rats, most of the paliperidone-related radioactivity (86%) was excreted in the feces. In dogs, the majority of the drug was excreted in the urine.
Drug Interactions
Paliperidone, at relevant clinical concentrations, had no or only marginal inhibitory effects on the major cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Risperidone exhibited no effects in vivo on any of the cytochrome P450 isoenzyme activities measured, or on UDP-glucuronosyltransferase activity. In vitro studies with Caco-2 cells indicated that paliperidone appears to have a weak P-glycoprotein inhibitory effect.
3.2.3 Toxicology
Single-Dose Toxicity
The toxicity of single doses of paliperidone were investigated in mice and rats via oral and intravenous routes. Approximate non-lethal oral doses of >80 mg/kg in mice and >20-40 mg/kg in rats were observed. With single intravenous bolus administration of paliperidone, no drug-related mortalities were seen at dose levels up to 10 mg/kg in mice and 40 mg/kg in rats. Sedation and ptosis were consistently noted across rodent species and routes of administration.
Repeat-Dose Toxicity
Toxicity findings related to exaggerated pharmacology, especially due to the dopamine D2 antagonist activity, were numerous. Treatment-related sedation and palpebral ptosis were consistently observed with paliperidone or risperidone in mice, rats, rabbits, and dogs. In addition, enhanced prolactin release was associated with changes in the following tissues: pituitary gland, mammary gland, endocrine pancreas, female genital tract, male accessory sex organs, and adrenal glands. Changes in body weight, body weight gain, and food consumption were noted. Treatment-related changes related to the antiadrenergic activity were also seen in the red pulp of the spleen in paliperidone- and risperidone-treated rats and dogs. Furthermore, QTc prolongation and testes effects, probably unrelated to exaggerated pharmacology, were observed in dogs. The observed toxicities were seen at systemic exposures in rats and mice below the human exposure (12 mg paliperidone). In dogs, the systemic exposure was approximately at or slightly above the clinical exposure. Similar toxicity profiles were seen after administration of paliperidone and risperidone.
Genotoxicity
The genotoxicity of paliperidone was studied with respect to gene mutations in bacteria, in mouse lymphoma cells, and in the rat micronucleus test in bone marrow. No genotoxic potential was observed in the test systems when tested with the appropriate concentrations and dose levels.
Carcinogenicity
Carcinogenicity studies conducted with risperidone in mice and rats showed treatment-related tumour findings in the mammary gland, endocrine pancreas, and pituitary gland.
Reproduction Toxicity
Paliperidone was not teratogenic in rats and rabbits. In rats at the maternally toxic dose of 2.5 mg/kg/day, there was a slight increase in pre-implantation loss resulting in fewer implantations and a lower number of live fetuses. Similar effects were seen with risperidone. In rabbits, total post-implantation loss was slightly increased at the high dose level of 5 mg/kg/day. This implantation loss was associated with a slight increase in the number of embryonic/fetal resorptions and fetal death.
Photosafety
An in vitro phototoxicity test was performed because paliperidone absorbs light in the wavelength from 290-329 nm and reaches the eyes following systemic exposure. The results were negative and the sponsor provided acceptable justification for the lack of additional photosafety studies.
3.2.4 Summary and Conclusion
Paliperidone is the major active metabolite of risperidone and is pharmacologically very similar to the parent compound. In vitro, paliperidone and risperidone shared similar binding affinity for 5-HT2A and D2 receptors. In standard comparative in vivo pharmacology studies, paliperidone and risperidone showed similar effects at closely related doses. All toxicity findings were similar to those observed with risperidone, except for QT prolongation which was observed in dogs at systemic exposures similar to predicted clinical exposures.
The non-clinical studies for this drug submission are considered suitable. Adequate statements are in place in the Product Monograph to address the identified safety concerns. In view of the intended use of Invega, there are no pharmacological/toxicological issues within the submission which preclude approval of the requested product indication.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
An extensive clinical pharmacology program for the pharmacodynamic (PD) and pharmacokinetic (PK) profile of paliperidone was performed comprising of 15 clinical pharmacology and 13 biopharmaceutical studies in healthy volunteers, schizophrenic patients and special populations. In addition, population PK analyses and in vitro studies were performed. Immediate-release (IR) formulations were used in the initial studies and subsequently the development was focused on extended-release (ER) formulations.
3.3.2 Pharmacodynamics
Paliperidone is a monoaminergic antagonist with a high affinity for serotoninergic (5hydroxytryptamine [5-HT] Type 2A [5HT2A]) and dopaminergic D2 receptors. Paliperidone binds also to α1-adrenergic receptors, and, with lower affinity, to H1-histaminergic and α2-adrenergic receptors. It has no affinity for cholinergic, muscarinic, or β1- and β2-adrenergic receptors.
Paliperidone is the main metabolite of risperidone and the pharmacological profile of paliperidone was very similar to that of risperidone. No essential new PD effects were observed nor were they expected.
One of the reasons for developing an ER formulation was to allow treatment initiation with an efficacious dose without having to start at a lower dose in order to reduce the possibility of orthostatic side effects. Reduction of the occurrence of orthostatic hypotension at the start of therapy was the outcome used in the selection of the most desirable ER profile. There was no clear apparent relationship between the plasma concentrations of paliperidone and the pharmacologically active fraction of risperidone and the change in orthostatic systolic blood pressure in a study comparing the orthostatic tolerability of paliperidone ER and an IR formulation of risperidone in subjects with schizophrenia.
Serum prolactin concentrations were evaluated. After single or multiple dose administration of IR paliperidone in healthy subjects and subjects with schizophrenia, prolactin concentrations increased and peaked approximately 1-2 hours after dosing and decreased thereafter. An ascending plasma profile, due to the ER technology, resulted in similar prolactin exposure levels compared to a dose of IR risperidone that resulted in a similar exposure to the pharmacologically active fraction of either product in plasma (i.e., paliperidone and paliperidone + risperidone, respectively).
The effect of paliperidone on cardiovascular safety, particularly on QT/QTc prolongation, was assessed in a thorough cardiovascular safety study. The PK/PD analysis suggests that effects of paliperidone on QTc interval are complex and cannot be explained by plasma concentrations only.
3.3.3 Pharmacokinetics
Absorption
Invega ER tablets have a prolonged-release formulation based on a delivery system designed to deliver paliperidone in a controlled manner during a 24-hour period. The absolute oral bioavailability of paliperidone from Invega was 28% and the median time to reach maximum plasma concentration was in the range of 20-25 hours, clearly indicating the prolonged-release characteristics of the formulation. The intake of food along with the administration of Invega increased the exposure of paliperidone up to 50-60%.
Distribution
Paliperidone was rapidly distributed into tissues, with a volume of distribution of 487 L. Paliperidone distributed well into the brain. Within therapeutically relevant concentrations of 50 to 250 ng/mL, the plasma protein binding was 74% for paliperidone. Paliperidone was predominately bound to α1-acid glycoprotein and albumin.
Metabolism
Paliperidone is not metabolized to a large extent. Almost 60% of the dose was identified as unchanged paliperidone in the urine. Four metabolites were identified in the urine, none of which accounted for more than 6.5% of the dose. Two metabolites were identified in the feces. In studies with the administration of radiolabelled paliperidone, unchanged paliperidone represented approximately 97% of the total radioactivity in plasma.
In vitro test results also indicated limited metabolism, with some involvement of the isozymes, CYP2D6 and CYP3A4. Special dose recommendations or precautions are not warranted for patients who are poor metabolizers of CYP2D6 substrates.
Excretion
Paliperidone was mainly excreted in the urine (80% of a radiolabelled dose), while only a small part was excreted in feces (11%).
Drug Interactions
Based on the in vitro and in vivo PK properties of paliperidone, the probability of drug-drug interactions is low. Considering the primary effects of paliperidone on the central nervous system, paliperidone should be administered with caution in combination with other centrally active drugs. Paliperidone may antagonize the effects of levodopa and other dopamine agonists. Due to its α1- and α2-adrenergic receptor antagonism, paliperidone has the potential to enhance the effect of certain antihypertensive agents. Appropriate information has been included in the Product Monograph.
Special Populations
Renal Impairment
The dose should be reduced in patients with moderate or severe renal impairment. Exposure to paliperidone was increased on average 2.1-3.4-fold in patients with severe renal impairment compared with healthy subjects and the mean half-life of the drug was increased to >50 hours.
Hepatic Impairment
Based on total plasma levels, the exposure to paliperidone was decreased in patients with moderate hepatic impairment (Child Pugh class B) compared with healthy subjects. However, plasma protein binding was lower in the hepatically impaired subjects resulting in a higher unbound fraction of paliperidone. After correcting for the difference in plasma protein binding the unbound exposure was similar in both groups. As severe hepatic impairment has not been studied, caution should be recommended in such patients. No dose adjustment is required in patients with mild or moderate hepatic impairment.
3.3.4 Clinical Efficacy
Four clinical studies were submitted to support the efficacy of Invega: three short-term Phase III studies (Studies 303, 304, and 305), and a relapse prevention study, Study 301. Overall, the clinical program was adequate with respect to experimental design, diagnostic criteria, and study endpoints.
Studies 303, 304, and 305 were placebo-controlled, double-blind, 6-week studies in non-elderly patients (n=1665, mean age 37 years) with schizophrenia. The doses of Invega ranged from 3 to 15 mg/day and an active control (olanzapine) was included as an active reference. The primary endpoint was the decrease in total Positive and Negative Syndrome Scale (PANSS) scores from baseline to endpoint.
The outcome of the three short-term studies compared well with what has been demonstrated for other drugs for the treatment of an acute episode of schizophrenia. A consistent effect for all doses relative to placebo was demonstrated and the magnitude of effect was similar to the effect of olanzapine. The difference compared to placebo in change from baseline in PANSS total score ranges was between -7 and -19 across the short-term studies with most of the comparisons between -13 and -19. There were 16% to 34% more responders, i.e., those with =30% decrease from baseline in PANSS total score in the Invega dose groups compared to placebo across the three short-term studies. Several adverse events were reported more frequently for the 15 mg dose, therefore the recommended dose range (3-12 mg) seems reasonable.
Within the recommended dose range, there were more adverse events with the higher dose, in particular 26% experienced extrapyramidal symptoms on 12 mg compared to 10% on 6 mg. Thus, the recommended starting dose (6 mg) seems reasonable as well.
A significant, but less pronounced effect was demonstrated in elderly patients (65 years of age or older) according to the results demonstrated in Study 302, which was a placebo-controlled, double-blind study in elderly patients.
Study 301 was designed as a relapse prevention study, but was considered to be a study more reflective of acute efficacy. Clinically stable patients with schizophrenia who were maintained on Invega for 8 weeks (doses from 3 to 15 mg/day) were randomized to either Invega at their achieved stable dose or to placebo. The primary endpoint was time to first psychiatric relapse. Twice as many patients in the placebo group (51.5%) experienced a relapse compared to patients treated with Invega (22.1%).
3.3.5 Clinical Safety
At the time of the Marketing Authorization Application submission, the combined exposure to Invega in all of the Phase III studies (complete and ongoing) was 921.31 patient-years for the 2,054 patients with schizophrenia who received at least one dose of Invega (3 mg to 15 mg). Based on the cumulative safety results presented up to the cut-off date of June 26, 2006, the combined exposure to Invega in the Phase III studies with the 2,054 adult patients plus elderly patients with schizophrenia was 1092.88 patient-years. Within all of the Phase III studies, 562 patients were treated for more than one year.
Up to the cut-off date of June 26, 2006 (August 31, 2006 for deaths and other serious adverse events), there were a total of 10 deaths in all of the completed and ongoing studies of Invega. The most common treatment-related adverse drug reactions were atrioventricular block, bradycardia, sinus tachycardia, tachycardia, bundle branch block, abdominal pain upper, dry mouth, salivary hypersecretion, vomiting, asthenia, fatigue, weight increased, headache, akathisia, dizziness, dystonia, extrapyramidal disorder, hypertonia, Parkinsonism, sedation, somnolence, tremor and orthostatic hypotension.
Asymptomatic increases of serum prolactin levels were also very frequent. Overall, the discontinuation rate due to adverse events was similar for patients treated with placebo compared to patients treated with Invega. From the safety database, all the adverse reactions reported in the clinical studies have been included in the Product Monograph.
A thorough QTc study in humans showed that paliperidone caused a modest increase in the corrected QT interval, approximately a maximal 9 milliseconds increase after administration with a 4 mg immediate release formulation (approximately equivalent to the maximum recommended dose of 12 mg Invega) was observed. The Warnings and Precautions section of the Invega Product Monograph recommends that: the use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. This is in accordance with the QT/QTc Interval Prolongation: Guidance for Product Monograph Content.
Overall, the safety profile is as expected for an active metabolite of risperidone.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/risk assessment
The efficacy of Invega in the treatment of schizophrenia was demonstrated relative to placebo and with a magnitude similar to the active comparator olanzapine. The extended-release formulation of Invega may enhance initial tolerability and permit initiation of treatment without the need for dose titration. Human PK studies have shown a food interaction, which may increase the variability in exposure; however, given the dosage recommendations and the nature of the patient population to be treated, it is not considered necessary or realistic to require standardization of dosing with food intake.
In non-clinical studies, paliperidone (the medicinal ingredient of Invega and an active metabolite of risperidone) and risperidone demonstrated similar pharmacological and toxicological profiles.
In the clinical studies, the safety profile for Invega was as expected for an active metabolite of risperidone and appeared similar to that of risperidone. An advantage of Invega is that it is not metabolized by cytochrome P450 enzymes, and does not induce or inhibit them. Consequently, hepatic drug interactions are not expected to be an issue. The effects on QT prolongation are modest and manageable through labelling.
The safety and efficacy profile of Invega is further supported by the extensive market experience with risperidone, which acts principally through paliperidone, its major metabolite.
Overall, the benefits of Invega therapy for schizophrenia outweigh the risks. The available information indicates that the risks associated with the use of Invega in adults with schizophrenia are acceptable and similar to risperidone at the recommended doses.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Invega is favourable in the treatment of schizophrenia. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Invega
| Submission Milestone | Date |
|---|---|
| Submission filed | 2006-09-27 |
| Screening | |
| Screening Deficiency Notice issued | 2006-11-10 |
| Response filed | 2006-11-14 |
| Screening Acceptance Letter issued | 2006-11-30 |
| Review | |
| Biopharmaceutics Evaluation complete | 2007-09-26 |
| Quality Evaluation complete | 2007-09-21 |
| Clinical Evaluation complete | 2007-09-26 |
| Labelling Review complete | 2007-09-26 |
| NOC issued by Director General | 2007-09-26 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| INVEGA | 02300303 | JANSSEN INC | PALIPERIDONE 9 MG |
| INVEGA | 02300281 | JANSSEN INC | PALIPERIDONE 6 MG |
| INVEGA | 02300273 | JANSSEN INC | PALIPERIDONE 3 MG |