Dosage Form: tablet, extended release
FULL PRESCRIBING INFORMATION
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Invega® SUSTENNA® (paliperidone palmitate) is not approved for the treatment of patients with dementia-related psychosis. [See Warnings and Precautions (5.1)]
Indications and Usage for Invega
Invega® SUSTENNA® (paliperidone palmitate) is indicated for the acute and maintenance treatment of schizophrenia in adults [see Clinical Studies (14)].
Invega Dosage and Administration
Recommended Dosing
For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with Invega® SUSTENNA®.
Recommended initiation of Invega® SUSTENNA® is with a dose of 234 mg on treatment day 1 and 156 mg one week later, both administered in the deltoid muscle. The recommended monthly maintenance dose is 117 mg; some patients may benefit from lower or higher maintenance doses within the recommended range of 39 to 234 mg based on individual patient tolerability and/or efficacy. Following the second dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle.
Adjustment of the maintenance dose may be made monthly. When making dose adjustments, the prolonged-release characteristics of Invega® SUSTENNA® should be considered [see Clinical Pharmacology (12.3)], as the full effect of the dose adjustment may not be evident for several months.
Missed Doses
Avoiding Missed Doses
It is recommended that the second initiation dose of Invega® SUSTENNA® be given one week after the first dose. To avoid a missed dose, patients may be given the second dose 2 days before or after the one-week timepoint. Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly. To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly timepoint.
Missed Dose (1 Month to 6 Weeks)
After initiation, the recommended injection cycle of Invega® SUSTENNA® is monthly. If less than 6 weeks have elapsed since the last injection, then the previously stabilized dose should be administered as soon as possible, followed by injections at monthly intervals.
Missed Dose (> 6 Weeks to 6 Months)
If more than 6 weeks have elapsed since the last injection of Invega® SUSTENNA®, resume the same dose the patient was previously stabilized on (unless the patient was stabilized on a dose of 234 mg, then the first two injections should each be 156 mg) in the following manner: 1) a deltoid injection as soon as practically possible, followed by 2) another deltoid injection (same dose) one week later, and 3) resumption of either deltoid or gluteal dosing at monthly intervals.
Missed Dose (> 6 Months)
If more than 6 months have elapsed since the last injection of Invega® SUSTENNA®, initiate dosing as described in Section 2.1 above.
Administration Instructions
Invega® SUSTENNA® is intended for intramuscular use only. Inject slowly, deep into the muscle. Care should be taken to avoid inadvertent injection into a blood vessel. Each injection should be administered by a health care professional. Administration should be in a single injection. Do not administer the dose in divided injections. Do not administer intravascularly or subcutaneously.
The recommended needle size for administration of Invega® SUSTENNA® into the deltoid muscle is determined by the patient's weight. For those ≥ 90 kg (≥ 200 lb), the 1½-inch, 22 gauge needle is recommended. For those < 90 kg (< 200 lb), the 1-inch, 23 gauge needle is recommended. Deltoid injections should be alternated between the two deltoid muscles.
The recommended needle size for administration of Invega® SUSTENNA® into the gluteal muscle is the 1½-inch, 22 gauge needle. Administration should be made into the upper-outer quadrant of the gluteal area. Gluteal injections should be alternated between the two gluteal muscles.
Use with Oral Paliperidone or with Risperidone
Concomitant use of Invega® SUSTENNA® with oral paliperidone or oral or injectable risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if any of these medications are coadministered with Invega® SUSTENNA®.
Dosage in Special Populations
Renal Impairment
Invega® SUSTENNA® has not been systematically studied in patients with renal impairment [see Clinical Pharmacology (12.3)]. For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min), recommended initiation of Invega® SUSTENNA® is with a dose of 156 mg on treatment day 1 and 117 mg one week later, both administered in the deltoid muscle. Thereafter, follow with monthly injections of 78 mg in either the deltoid or gluteal muscle.
Invega® SUSTENNA® is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min).
Hepatic Impairment
Invega® SUSTENNA® has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment. [See Clinical Pharmacology (12.3)]
Elderly
In general, recommended dosing of Invega® SUSTENNA® for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. As elderly patients may have reduced renal function, see Renal Impairment above for dosing recommendations in patients with renal impairment.
Maintenance Therapy
Invega® SUSTENNA® has been shown to be effective in delaying time to relapse of symptoms of schizophrenia in long-term use. It is recommended that responding patients be continued on treatment at the lowest dose needed. Patients should be periodically reassessed to determine the need for continued treatment.
Switching from Other Antipsychotics
There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to Invega® SUSTENNA®, or concerning concomitant administration with other antipsychotics.
Switching from Oral Antipsychotics
For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with Invega® SUSTENNA®.
Previous oral antipsychotics can be discontinued at the time of initiation of treatment with Invega® SUSTENNA®. Invega® SUSTENNA® should be initiated as described in Section 2.1. Patients previously stabilized on different doses of Invega® Extended-Release tablets can attain similar paliperidone steady-state exposure during maintenance treatment with Invega® SUSTENNA® monthly doses as depicted in Table 1.
| Formulation | Invega® Extended-Release Tablet | Invega® SUSTENNA® Injection |
|---|---|---|
| Dosing Frequency | Once Daily | Once every 4 weeks |
| Dose (mg) | 12 6 3 | 234 117 39–78 |
Switching from Long-Acting Injectable Antipsychotics
For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral paliperidone or oral risperidone prior to initiating treatment with Invega® SUSTENNA®.
When switching patients from previous long-acting injectable antipsychotics, initiate Invega® SUSTENNA® therapy in place of the next scheduled injection. Invega® SUSTENNA® should then be continued at monthly intervals. The one-week initiation dosing regimen as described in Section 2.1 is not required.
If Invega® SUSTENNA® is discontinued, its prolonged-release characteristics must be considered. As recommended with other antipsychotic medications, the need for continuing existing extrapyramidal symptoms (EPS) medication should be re-evaluated periodically.
Instructions for Use
The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle and a 1-inch 23 gauge needle) for intramuscular injection.
Invega® SUSTENNA® is for single use only.
- 1.
- Shake the syringe vigorously for a minimum of 10 seconds to ensure a homogeneous suspension.
- 2.
- Select the appropriate needle.
For DELTOID injection, if the patient weighs < 200 lb (< 90 kg), use the 1-inch 23 gauge needle (needle with blue colored hub); if the patient weighs ≥ 200 lb (≥ 90 kg), use the 1 ½-inch 22 gauge needle (needle with gray colored hub).
For GLUTEAL injection, use the 1 ½-inch 22 gauge needle (needle with gray colored hub).
- 3.
- While holding the syringe upright, remove the rubber tip cap with an easy clockwise twisting motion.
- 4.
- Peel the safety needle pouch half way open. Grasp the needle sheath using the plastic peel pouch. Attach the safety needle to the luer connection of the syringe with an easy clockwise twisting motion.
- 5.
- Pull the needle sheath away from the needle with a straight pull. Do not twist the sheath as the needle may be loosened from the syringe.
- 6.
- Bring the syringe with the attached needle in upright position to de-aerate. De-aerate the syringe by moving the plunger rod carefully forward.
- 7.
- Inject the entire contents intramuscularly into the selected deltoid or gluteal muscle of the patient. Do not administer intravascularly or subcutaneously.
- 8.
- After the injection is complete, use either thumb or finger of one hand (8a, 8b) or a flat surface (8c) to activate the needle protection system. The needle protection system is fully activated when a 'click' is heard. Discard the syringe with needle appropriately.
| 8a | |
| 8b | |
| 8c | |
Dosage Forms and Strengths
Invega® SUSTENNA® is available as a white to off-white aqueous extended-release suspension for intramuscular injection in dose strengths of 39 mg, 78 mg, 117 mg, 156 mg, and 234 mg paliperidone palmitate.
Contraindications
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone and paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone and is therefore contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the Invega® SUSTENNA® formulation.
Warnings and Precautions
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Invega® SUSTENNA® (paliperidone palmitate) is not approved for the treatment of dementia-related psychosis [see Boxed Warning].
Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients With Dementia-Related Psychosis
In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. Oral paliperidone and Invega® SUSTENNA® were not marketed at the time these studies were performed and are not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].
Neuroleptic Malignant Syndrome
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported.
QT Prolongation
Paliperidone causes a modest increase in the corrected QT (QTc) interval. 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.
Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
The effects of oral paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.
In the QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate release (Cmax ss = 113 ng/mL) was more than 2-fold the exposure observed with the maximum recommended 234 mg dose of Invega® SUSTENNA® administered in the deltoid muscle (predicted median Cmax ss = 50 ng/mL). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which Cmax ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose.
In the three fixed-dose efficacy studies of oral paliperidone extended release, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the oral paliperidone 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec).
In the four fixed-dose efficacy studies of Invega® SUSTENNA®, no subject experienced a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point. In the maintenance study, no subject had a QTcLD change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett's QT corrected interval [QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.
Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.
There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.
Given these considerations, Invega® SUSTENNA® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with Invega® SUSTENNA®, drug discontinuation should be considered. However, some patients may require treatment with Invega® SUSTENNA® despite the presence of the syndrome.
Metabolic Changes
Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes in trial subjects treated with Invega® SUSTENNA®. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because Invega® SUSTENNA® was not marketed at the time these studies were performed, it is not known if Invega® SUSTENNA® is associated with this risk.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 2.
| Invega® SUSTENNA® | |||||||
|---|---|---|---|---|---|---|---|
| Placebo | 39 mg | 78 mg | 156 mg | 234/39 mg* | 234/156 mg* | 234/234 mg* | |
| Mean change from baseline (mg/dL) | |||||||
| n=367 | n=86 | n=244 | n=238 | n=110 | n=126 | n=115 | |
| |||||||
| Serum Glucose Change from baseline | -1.3 | 1.3 | 3.5 | 0.1 | 3.4 | 1.8 | -0.2 |
| Proportion of Patients with Shifts | |||||||
| Serum Glucose Normal to High | 4.6% | 6.3% | 6.4% | 3.9% | 2.5% | 7.0% | 6.6% |
| (<100 mg/dL to ≥126 mg/dL) | (11/241) | (4/64) | (11/173) | (6/154) | (2/79) | (6/86) | (5/76) |
In a long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, Invega® SUSTENNA® was associated with a mean change in glucose of -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100).
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 3.
| Invega® SUSTENNA® | |||||||
|---|---|---|---|---|---|---|---|
| Placebo | 39 mg | 78 mg | 156 mg | 234/39 mg* | 234/156 mg* | 234/234 mg* | |
| |||||||
| Mean change from baseline (mg/dL) | |||||||
| Cholesterol | n=366 | n=89 | n=244 | n=232 | n=105 | n=119 | n=120 |
| Change from baseline | -6.6 | -6.4 | -5.8 | -7.1 | -0.9 | -4.2 | 9.4 |
| LDL | n=275 | n=80 | n=164 | n=141 | n=104 | n=117 | n=108 |
| Change from baseline | -6.0 | -4.8 | -5.6 | -4.8 | 0.9 | -2.4 | 5.2 |
| HDL | n=286 | n=89 | n=165 | n=150 | n=105 | n=118 | n=115 |
| Change from baseline | 0.7 | 2.1 | 0.6 | 0.3 | 1.5 | 1.1 | 0.0 |
| Triglycerides | n=366 | n=89 | n=244 | n=232 | n=105 | n=119 | n=120 |
| Change from baseline | -16.7 | 7.6 | -9.0 | -11.5 | -14.1 | -20.0 | 11.9 |
| Proportion of Patients with Shifts | |||||||
| Cholesterol | |||||||
| Normal to High | 3.2% | 2.0% | 2.0% | 2.1% | 0% | 3.1% | 7.1% |
| (<200 mg/dL to ≥240 mg/dL) | (7/222) | (1/51) | (3/147) | (3/141) | (0/69) | (2/65) | (6/84) |
| LDL | |||||||
| Normal to High | 1.1% | 0% | 0% | 0% | 0% | 0% | 0% |
| (<100 mg/dL to ≥160 mg/dL) | (1/95) | (0/29) | (0/67) | (0/46) | (0/41) | (0/37) | (0/44) |
| HDL | |||||||
| Normal to Low | 13.8% | 14.8% | 9.6% | 14.2% | 12.7% | 10.5% | 16.0% |
| ( ≥40 mg/dL to <40 mg/dL) | (28/203) | (9/61) | (11/115) | (15/106) | (9/71) | (8/76) | (13/81) |
| Triglycerides | |||||||
| Normal to High | 3.6% | 6.1% | 9.2% | 7.2% | 1.3% | 3.7% | 10.7% |
| (<150 mg/dL to ≥200 mg/dL) | (8/221) | (3/49) | (14/153) | (10/139) | (1/79) | (3/82) | (9/84) |
In a long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, Invega® SUSTENNA® was associated with a mean change in (a) total cholesterol of -1.2 mg/dL at Week 29 (n=112) and +0.1 mg/dL at Week 53 (n=100); (b) LDL of -2.7 mg/dL at Week 29 (n=107) and -2.3 mg/dL at Week 53 (n=89); (c) HDL of -0.8 mg/dL at Week 29 (n=112) and -2.6 mg/dL at Week 53 (n=98); and (d) triglycerides of +16.2 mg/dL at Week 29 (n=112) and +37.4 mg/dL at Week 53 (n=100).
Weight Gain
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 4.
| Invega® SUSTENNA® | |||||||
|---|---|---|---|---|---|---|---|
| Placebo | 39 mg | 78 mg | 156 mg | 234/39 mg* | 234/156 mg* | 234/234 mg* | |
| n=451 | n=116 | n=280 | n=267 | n=137 | n=144 | n=145 | |
| |||||||
| Weight (kg) Change from baseline | -0.4 | 0.4 | 0.8 | 1.4 | 0.4 | 0.7 | 1.4 |
| Weight Gain ≥ 7% increase from baseline | 3.3% | 6.0% | 8.9% | 9.0% | 5.8% | 8.3% | 13.1% |
In a long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, Invega® SUSTENNA® was associated with a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at Week 53 (n=113).
Hyperprolactinemia
Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.
Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.
Orthostatic Hypotension and Syncope
Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-blocking activity. Syncope was reported in < 1% (4/1293) of subjects treated with Invega® SUSTENNA® in the recommended dose range of 39 mg to 234 mg in the four fixed-dose, double-blind, placebo-controlled trials compared with 0% (0/510) of subjects treated with placebo. In the four fixed-dose efficacy studies, orthostatic hypotension was reported as an adverse event by < 1% (2/1293) of Invega® SUSTENNA®-treated subjects compared to 0% (0/510) with placebo. Incidences of orthostatic hypotension and syncope in the long-term studies were similar to those observed in the short-term studies.
Invega® SUSTENNA® should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.
Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including Invega®, an oral form of paliperidone. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of Invega® SUSTENNA® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Invega® SUSTENNA® and have their WBC followed until recovery.
Potential for Cognitive and Motor Impairment
Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with Invega® SUSTENNA®[see Adverse Reactions (6.1)]. Antipsychotics, including Invega® SUSTENNA®, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.
Seizures
In the four fixed-dose double-blind placebo-controlled studies, <1% (1/1293) of subjects treated with Invega® SUSTENNA® in the recommended dose range of 39 mg to 234 mg experienced an adverse event of convulsion compared with <1% (1/510) of placebo-treated subjects who experienced an adverse event of grand mal convulsion.
Like other antipsychotic drugs, Invega® SUSTENNA® should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.
Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Invega® SUSTENNA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
Suicide
The possibility of suicide attempt is inherent in psychotic illnesses, and close supervision of high-risk patients should accompany drug therapy.
Priapism
Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with Invega® SUSTENNA®, priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.
Thrombotic Thrombocytopenic Purpura (TTP)
No cases of TTP were observed during clinical studies with oral paliperidone or Invega® SUSTENNA®. Although cases of TTP have been reported in association with risperidone administration, the relatio
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