Pharmaceutical Approval Update

Posted by James

Paliperidone (Invega)

Manufacturer: Janssen (J&J), Titusville, NJ

Indication: Paliperidone, an extended-release tablet, is an atypical antipsychotic agent indicated for the treatment of schizophrenia.

Drug Class: This psychotropic agent belongs to the chemical class of benzisoxazole derivatives. It contains a racemic mixture of (+)- and (-)- paliperidone.

The chemical name is (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C₂₃H₂₇FN₄O₃ with a molecular weight of 426.49.

Uniqueness of Product: The tablets are available in 3-mg (white), 6-mg (beige), and 9-mg (pink) strengths. OROS technology (Alza Corp.) employs osmotic pressure to deliver paliperidone at a controlled rate.

The delivery system, which resembles a capsule-shaped tablet in appearance, consists of an osmotically active triple-layer core, surrounded by a subcoat and a semipermeable membrane. This core is composed of two layers containing the drug with excipients and a “push” layer containing osmotically active components. The push layer helps release the drug from the delivery system. There are two precision laser-drilled orifices on the drug-layer dome of the tablet.

Each strength of the tablet has a water-dispersible overcoat and print markings in a different color. In an aqueous environment, such as the gastrointestinal (GI) tract, the water-dispersible color overcoat erodes quickly. Water then enters the tablet through the semipermeable membrane, which controls the rate at which water enters the tablet core. The core, in turn, determines the rate of drug delivery.

The hydrophilic polymers of the core become hydrated and swell, creating a gel containing paliperidone. The gel is then pushed out through the tablet orifices. The biologically inert components of the tablet remain intact during transit within the GI tract and are eliminated in the stool as a tablet shell, along with insoluble core components.

Boxed Warning:

Increased mortality in elderly patients with dementia-related psychosis: Elderly patients with dementia-related psychosis who take atypical antipsychotic drugs are at an increased risk of death compared with those taking placebo. Analyses of 17 placebo-controlled trials (modal duration, 10 weeks) revealed a risk of death in the drug-treated subjects of between 1.6 and 1.7 times that seen in placebo-treated subjects. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated subjects was about 4.5%, compared with a rate of about 2.6% in the placebo patients. Although the causes of death varied, most deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Paliperidone is not approved for patients with dementia-related psychosis.

Warnings:

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 (quinidine, procainamide) or Class III (amiodarone drug, canadian sotalol) antiarrhythmic medications, anti-psychotic medications (generic chlorpromazine, thioridazine), antibiotics (generic gatifloxacin, moxifloxacin tablet), or any other class of agents known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in those with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of torsades de pointes or sudden death in association with the use of drugs that prolong the QTc interval, including:

• bradycardia.
• hypokalemia or hypomagnesemia.
• the concomitant use of other drugs that prolong the QTc interval.
• the presence of congenital prolongation of the QT interval.

Neuroleptic malignant syndrome: This potentially fatal symptom complex has been reported in association with anti-psychotic drugs, including paliperidone. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac dys-rhythmia). Additional signs of the syndrome may include elevated creatine phosphokinase levels, myoglobinuria (rhab-domyolysis), and acute renal failure.

The diagnostic evaluation of patients with the 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) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

Tardive dyskinesia: A syndrome of potentially irreversible, involuntary movements may develop in patients who take anti-psychotic drugs. The prevalence of the tardive dyskinesia appears to be highest among the elderly, especially women.

It is not possible to truly know whether atypical antipsychotic drugs have less potential to cause tardive dyskinesia than do the older drugs. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase with the duration of treatment and the total cumulative dose. However, the syndrome can also develop after relatively brief treatment periods at low doses, although this is uncommon.

Long-term treatment with antipsychotic drugs should generally be reserved for patients with a chronic illness that is known to respond to these drugs. In patients who do require chronic treatment, physicians should prescribe the smallest dose and the shortest duration of treatment that produces a satisfactory clinical response. The need for continued treatment should be reassessed periodically.

Hyperglycemia and diabetes mellitus: All atypical anti-psychotic agents have been reported to cause hyperglycemia. In some cases, hyperglycemia was extreme and associated with ketoacidosis or hyperosmolar coma or death. These cases were usually noted in postmarketing studies, not in clinical trials. There have been few reports of hyperglycemia or diabetes in trial subjects receiving paliperidone.

Assessment of the relationship between the use of atypical antipsychotic drugs 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 anti-psychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyper-glycemia-related adverse events in patients treated with the atypical antipsychotic agents. Because paliperidone was not marketed at the time these studies were performed, it is not known whether the agent is associated with this increased risk.

Patients with diabetes mellitus who begin a regimen of atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes (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.

All patients taking atypical antipsychotic agents should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, and weakness). Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotic medications should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the drug was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Gastrointestinal effects: Because the paliperidone tablet is non-deformable and does not appreciably change in the GI tract, it should not ordinarily be given to patients with preexisting severe GI tract narrowing (e.g., esophageal motility disorders, small-bowel inflammatory disease, short-gut syndrome, peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel’s diverticulum).

There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in non-deformable, controlled-release formulations. Because of the controlled-release design of the tablet, paliperi-done should be used only in patients who can swallow the tablet whole. A decrease in transit time, as seen with diarrhea, would be expected to decrease the drug’s bioavailability. An increase in transit time, as seen with GI neuropathy, diabetic gastroparesis, or other causes, would be expected to increase bioavailability. These changes in bioavailability are more likely when changes in transit time occur in the upper GI tract.

Dosage and Administration: The recommended dose of paliperidone extended-release tablets is 6 mg once daily, taken in the morning. Titration of the initial dose is not required. Although it has not been systematically established that doses above 6 mg have additional benefit, there was a general trend for greater effects with higher doses. This must be weighed against the dose-related increase in adverse effects. Thus, some patients may benefit from higher doses, up to 12 mg/day. For other patients, a lower dose of 3 mg/day may be sufficient.

Dose increases above 6 mg/day should be made only after clinical reassessment, and they generally should occur at intervals of more than five days. When an increase in dose is indicated, small increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day.
Paliperidone may be taken with or without food.

Renal impairment: Dosing must be individualized according to the patient’s renal function status. For patients with mild renal impairment (a creatinine clearance [CrCl] between 50 and 80 ml/minute), the maximum recommended dose is 6 mg once daily. For patients with moderate-to-severe renal impairment (a CrCl between 10 and 50 ml/minute), the maximum recommended dose of paliperidone is 3 mg once daily.

Hepatic impairment: For patients with mild-to-moderate hepatic impairment, (Child-Pugh Classification A and B), no dose adjustment is recommended.

Commentary: Schizophrenia is a chronic and often debilitating mental illness that can cause the patient to withdraw from people and activities and to retreat into a world of delusions. It is a form of psychosis and a symptom of disordered brain function. In this type of impaired thinking, patients misinterpret reality. The illness affects approximately 1% of the population worldwide. In men, schizophrenia typically emerges in the teens or 20s. In women, the onset of schizophrenia is typically in the 20s or early 30s. There is often no cure, but newer medications continue to make this poorly understood disease more manageable.

The once-a-day tablet is derived from risperidone medication (Risperdal canadian, Janssen), another atypical antipsychotic drug used to treat schizophrenia, but paliperidone has an additional hydroxyl group. In clinical studies, paliperidone was more effective than placebo in relieving schizophrenia symptoms. However, with­out studies comparing paliperidone with other schizophrenia drugs, paliperidone has not yet proved superior to existing drugs.