Given the primary CNS effects of Nodiril, caution should be used when RISPERDAL® is taken in combination with other centrally-acting drugs and alcohol.
Nodiril has been assessed in treatment-resistant depression in a three-phase study: (i) 4–6 weeks of open citalopram monotherapy; (ii) 4–6 weeks of open Nodiril augmentation; (iii) a 24-week randomized double-blind phase (Nodiril, n = 122; placebo, n = 119) (167 c ) . A total of 489 patients with major depressive disorder and 1–3 documented treatment failures entered the citalopram monotherapy phase (20–60 mg/day). In phase 2, the most frequent adverse events were dry mouth, headache, and dizziness; there were no significant changes in different extrapyramidal symptom scales. At end-point, the mean prolactin concentration was 35 ng/ml with Nodiril versus 6.6 ng/ml with placebo; galactorrhea was reported in 2.5% of patients taking Nodiril and none of those taking placebo. The proportion of patients who gained 7% or more of body weight from baseline to end-point in phase 2 was 3.1% (all of them taking Nodiril) and 8.3% and 2.6% in those taking Nodiril or placebo respectively during phase 3; mean weight changes in this third phase were 1.3 kg and –0.5 kg respectively. Mean Nodiril modal doses were 1.1 mg/day in phase 2 and 1.2 mg/day in phase 3.
There has been some focus on children and adolescents with disruptive behavior disorder. In a study supported by Johnson & Johnson patients aged 5–17 years, without moderate or severe intellectual impairment, and with conduct disorder (n = 390), oppositional defiant disorder (n = 318), or other diagnoses (n = 19) were studied; 349 children also had attention deficit disorder with hyperactivity (168 C ) . Patients who had responded to risper >
In a randomized, double-blind study, 68 patients with schizophrenia and a poor response to clozapine were randomly assigned to augmentation with risper >(169 c ) . There was no statistically significant difference in symptomatic benefit between Nodiril and placebo. The increase in fasting blood glucose concentrations was slightly greater with Nodiril group than placebo.
Getting the most from your treatment
- Remember to keep your regular doctor's appointments so that your progress can be checked. If you are taking Nodiril long-term, you may need to have some tests from time to time.
- If you drink alcohol, ask your doctor for advice about drinking while you are on Nodiril. Alcohol will increase the chance that you experience side-effects and is unlikely to be recommended for you.
- If you are having an operation, tell the person carrying out the treatment which medicines you are taking. This is important because Nodiril may interfere with any anaesthetic you receive. If you are having cataract surgery, it is particularly important that you tell your surgeon you are on Nodiril. This is because an eye problem known as 'floppy iris syndrome' has developed in some people and your doctor will want to advise you about the risk of this.
- If you buy or take any 'over-the-counter' medicines, check with a pharmacist that they are suitable to take with Nodiril.
- If you have diabetes you may need to check your blood glucose more frequently as Nodiril can affect the levels of sugar in your blood. Your doctor will advise you about this.
- When Nodiril has been taken for a while, stopping treatment suddenly can cause problems. If you have been taking it regularly for a year or so, your doctor will probably want you to reduce your dose gradually if this becomes necessary.
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of Nodiril.
Interactions that increase your risk of side effects
Taking Nodiril with certain medications raises your risk of side effects from Nodiril. This is because the amount of Nodiril in your body is increased, or both medications may cause the same side effects. Examples of these drugs include:
- Anxiety drugs, such as alprazolam, clonazepam, diazepam, chlordiazepoxide, and lorazepam. You may have more sedation and drowsiness.
- Muscle relaxants, such as baclofen, cyclobenzaprine, methocarbamol, tizanidine, carisoprodol, and metaxalone. You may have more sedation and drowsiness.
- Pain drugs, such as morphine, oxycodone, fentanyl, hydrocodone, tramadol, and codeine. You may have more sedation and drowsiness.
- Antihistamines, such as hydroxyzine, diphenhydramine, chlorpheniramine, and brompheniramine. You may have more sedation and drowsiness.
- Sedative/hypnotics, such as zolpidem, temazepam, zaleplon, and eszopiclone. You may have more sedation and drowsiness.
- Fluoxetine. You may have increased risk of QT interval prolongation, irregular heart rhythm, and other side effects of Nodiril. Your doctor may decrease your Nodiril dose.
- Paroxetine. You may have increased risk of QT interval prolongation, irregular heart rhythm, and other side effects of Nodiril. Your doctor may decrease your Nodiril dose.
- Clozapine. You may have parkinsonism (trouble moving), sleepiness, anxiety, blurred vision, and other side effects of Nodiril. Your doctor will monitor you closely for side effects and toxicity.
- Blood pressure drugs, such as amlodipine, lisinopril, losartan, or metoprolol. You may have low blood pressure.
- Parkinson’s disease drugs,such as levodopa, pramipexole, or ropinirole. You may have more Parkinson’s disease symptoms.
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin levels and the elevation persists during chronic administration. RISPERDAL® is associated with higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin 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 contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the Nodiril carcinogenicity studies conducted in mice and rats . 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; the available evidence is considered too limited to be conclusive at this time.
The sections below will provide you with more specific information and guidelines related to Nodiril and its correct use. Please read them carefully.
In December 2003, physicians treating patients with bipolar mania gained a new treatment option with the FDA-approval of Nodiril (Risperdal®) used alone or in combination with lithium or valproate. The FDA approved Nodiril for the short-term treatment of acute manic or mixed episodes associated with bipolar disorder.
Nodiril is now the most commonly prescribed antipsychotic medication in the United States.
However, Nodiril has received a “not approved” letter from the FDA for use in autism.
Please visit the official site of the FDA for further information.
Why is this medication prescribed?
Nodiril is used for the treatment of psychotic disorders, for example, schizophrenia. It also is used in combination with lithium or valproate for the treatment of acute manic or mixed episodes associated with bipolar I disorder.
This medication works by interfering with the communication among nerves in the brain. The nerves communicate with one another by producing and releasing chemicals called neurotransmitters. The neurotransmitters attach to receptors on other nearby nerves, and the attachment of the neurotransmitter causes changes in the cells that have the receptor on them. Nodiril blocks several of the receptors on nerves including dopamine type 2, serotonin type 2, and alpha 2 adrenergic receptors and this blocks communication among nerves.
Nodiril is a relatively new antipsychotic medication that probably has fewer side effects than many of the older medications.
Other uses for this medicine
Nodiril has also been used to treat severe behavioral problems in children and teenagers, as well as in the treatment of irritability associated with autistic disorders. However, it is important to note that the FDA has warned that the safety of Nodiril in children has actually never been established.
Moreover, it is important that you talk to your doctor about the possible risks of using this drug for your particular condition.
Dosage and using this medicine
Nodiril comes as a tablet, a solution (liquid), and an orally disintegrating tablet to take by mouth.
It is usually taken once or twice a day with or without food.
Take Nodiril exactly as directed by your doctor. Do not take more or less of it or take it more often than prescribed by your doctor.
Use the dropper provided to measure your dose of Nodiril oral solution. You can take the oral solution with water, orange juice, coffee, or low-fat milk. Do not take the solution with tea or cola.
To take the orally disintegrating tablet, use dry hands to separate one blister unit at the perforation. Peel back the foil and remove the tablet. Do not push the tablet through the foil. Immediately place the entire tablet on your tongue but do not chew it. The tablet will quickly dissolve and may be swallowed with or without water.
Additionally, your doctor will probably start you on a low dose of Nodiril and gradually increase your dose every day for several days, and then not more than once every week.
Please note that Nodiril controls schizophrenia but does not cure it. It may take several weeks or longer before you feel the full benefit of Nodiril. Continue to take Nodiril even if you feel well, and never take Nodiril without first talking with your doctor. If you suddenly stop taking Nodiril, your symptoms may return and your illness may become harder to treat.
What special precautions should I follow?
Is Nodiril available as a generic drug?
GENERIC AVAILABLE: Yes, Nodiril. No, Risperdal Consta
Nodiril is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of Nodiril to 9-hydroxyNodiril by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyNodiril, has similar pharmacological activity as Nodiril. Consequently, the clinical effect of the drug results from the combined concentrations of Nodiril plus 9-hydroxyNodiril.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert Nodiril rapidly into 9-hydroxyNodiril, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower Nodiril and higher 9-hydroxyNodiril concentrations than poor metabolizers, the pharmacokinetics of Nodiril and 9-hydroxyNodiril combined, after single and multiple doses, are similar in extensive and poor metabolizers.
Nodiril could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of Nodiril to 9-hydroxyNodiril . This occurs with quinidine, giving essentially all recipients a Nodiril pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of Nodiril in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given RISPERDAL® do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause a decrease in the combined plasma concentrations of Nodiril and 9-hydroxyNodiril . It would also be possible for Nodiril to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of Nodiril to the enzyme suggests this is unlikely .
In vitro studies indicate that Nodiril is a relatively weak inhibitor of CYP 2D6. Therefore, RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly affect the pharmacokinetics of donepezil and galantamine, fwhich are metabolized by CYP 2D6.
In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of Nodiril metabolism.
RISPERDAL® is contraindicated in patients with a known hypersensitivity to either Nodiril or paliperidone, or to any of the excipients in the RISPERDAL® formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with Nodiril and in patients treated with paliperidone. Paliperidone is a metabolite of Nodiril.
RISPERDAL® contains Nodiril, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyridopyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
Nodiril is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® Tablets are for oral administration and available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL® tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn). The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The 0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution. RISPERDAL® Oral Solution contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and purified water.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg (light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL® M-TAB® Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite® resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric oxide, and peppermint oil. In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL® M-TAB® Orally Disintegrating Tablets contain xanthan gum.
Other Adverse Reactions Observed During The Clinical Trial Evaluation Of Nodiril
The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of RISPERDAL® in adults and pediatric patients.
Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia
Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block
Ear and Labyrinth Disorders: ear pain, tinnitus
Endocrine Disorders: hyperprolactinemia
Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced
Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism
General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal
Immune System Disorders: drug hypersensitivity
Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic
Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased
Metabolism and Nutrition Disorders: decreased appetite, polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint stiffness, joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis
Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement
Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema
Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular, acne, hyperkeratosis, seborrheic dermatitis
Vascular Disorders: hypotension, flushing
Interactions that can make your drugs less effective
When Nodiril is used with certain drugs, it may not work as well to treat your condition. This is because the amount of Nodiril in your body may be decreased. Examples of these drugs include:
- Phenytoin. Your doctor may increase your Nodiril dose.
- Carbamazepine. Your doctor may increase your Nodiril dose.
- Rifampin. Your doctor may increase your Nodiril dose.
- Phenobarbital. Your doctor may increase your Nodiril dose.
Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs interact differently in each person, we cannot guarantee that this information includes all possible interactions. This information is not a substitute for medical advice. Always speak with your healthcare provider about possible interactions with all prescription drugs, vitamins, herbs and supplements, and over-the-counter drugs that you are taking.
Risper > Nodiril is a benzisoxazole derivative approved by the FDA for treatment of schizophrenia in 1994, for short-term treatment of the mixed and manic states of bipolar disorder in 2003, and for treatment of irritability in children with autism in 2006. In 2007 it was approved as a treatment for schizophrenia and bipolar disorder in children. Its pharmacology is characterized by binding affinity for 5-HT 2A receptors that is 20 times that for D2-dopamine receptors. D2-receptor affinity is approximately 50 times, and 5-HT2A receptor affinity approximately 20 times that of clozapine. Nodiril also has strong affinity for α1-/α2-adrenergic and H1-histamine receptors. Affinity for D1 receptors is low, and it has no affinity at muscarinic receptors. Protein binding is 90%, and it is metabolized by CYP 2D6. D2-receptor occupancy at therapeutic doses is 63% to 89%, which would be expected to be associated with a significant incidence of EPS. 110 The addition of strong serotonergic antagonism, with a 5-HT2 receptor occupancy of 95%, is thought to confer protection against D2 antagonist effects on the nigrostriatal pathway, and the incidence of EPS is low. Nonetheless, unlike other SGAs with relatively lower affinities for D2 receptors that permit dynamic responses to surges in dopamine, Nodiril is tightly bound and does cause significant hyperprolactinemia. 111,112 It can also cause orthostatic hypotension during early treatment. Nodiril does not cause prolongation of the QTc and is less arrhythmogenic than other antipsychotics. It carries a boxed warning for increased risk of death in older patients receiving antipsychotics for dementia-related psychosis.
In healthy elderly subjects, renal clearance of both Nodiril and 9-hydroxyNodiril was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients .