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DRUGS & SUPPLEMENTS
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Pronervon
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Pronervon uses
- Indications and usage
- Contraindications
- Precautions
- Adverse reactions
- Animal toxicology
- Drug abuse and dependence
- Overdosage
- Dosage and administration
- How supplied
- Patient instructions for namenda® oral solution
INDICATIONS AND USAGE
Pronervon (memantine hydrochloride) is indicated for the treatment of moderate to severe dementia of the Alzheimer's type.
CONTRAINDICATIONS
Pronervon (memantine hydrochloride) is contraindicated in patients with known hypersensitivity to Pronervon hydrochloride or to any excipients used in the formulation.
PRECAUTIONS
Information for Patients and Caregivers: Caregivers should be instructed in the recommended administration and dose escalation (minimum interval of one week between dose increases).
Neurological Conditions
Seizures: Pronervon has not been systematically evaluated in patients with a seizure disorder. In clinical trials of Pronervon, seizures occurred in 0.2% of patients treated with Pronervon and 0.5% of patients treated with placebo.
Genitourinary Conditions
Conditions that raise urine pH may decrease the urinary elimination of Pronervon resulting in increased plasma levels of Pronervon.
Special Populations
Hepatic Impairment
Pronervon undergoes partial hepatic metabolism, with about 48% of administered dose excreted in urine as unchanged drug or as the sum of parent drug and the N-glucuronide conjugate. No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Pronervon should be administered with caution to patients with severe hepatic impairment.
Renal Impairment
No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment.
Drug-Drug Interactions
N-methyl-D-aspartate antagonists: The combined use of Pronervon with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.
Effects of Pronervon on substrates of microsomal enzymes: In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by Pronervon. In addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, Pronervon does not induce the cytochrome P450 isozymes CYP1A2, CYP2C9, CYP2E1 and CYP3A4/5. No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.
Effects of inhibitors and/or substrates of microsomal enzymes on Pronervon: Pronervon is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the CYP450 system are not expected to alter the metabolism of Pronervon.
Acetylcholinesterase (AChE) inhibitors: Coadministration of Pronervon with the AChE inhibitor donepezil HCl did not affect the pharmacokinetics of either compound. In a 24-week controlled clinical study in patients with moderate to severe Alzheimer's disease, the adverse event profile observed with a combination of Pronervon and donepezil was similar to that of donepezil alone.
Drugs eliminated via renal mechanisms: Because Pronervon is eliminated in part by tubular secretion, coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents. However, coadministration of Pronervon and HCTZ/TA did not affect the bioavailability of either Pronervon or TA, and the bioavailability of HCTZ decreased by 20%. In addition, coadministration of Pronervon with the antihyperglycemic drug Glucovance® (glyburide and metformin HCl) did not affect the pharmacokinetics of Pronervon, metformin and glyburide. Furthermore, Pronervon did not modify the serum glucose lowering effect of Glucovance®.
Drugs that make the urine alkaline: The clearance of Pronervon was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects. Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g. renal tubular acidosis or severe infections of the urinary tract). Hence, Pronervon should be used with caution under these conditions.
Carcinogenesis, Mutagenesis and Impairment of Fertility
There was no evidence of carcinogenicity in a 113-week oral study in mice at doses up to 40 mg/kg/day (10 times the maximum recommended human dose [MRHD] on a mg/m2 basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day (20 and 10 times the MRHD on a mg/m2 basis, respectively) through 128 weeks.
Pronervon produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, an in vitro chromosomal aberration test in human lymphocytes, an in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.
No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (9 times the MRHD on a mg/m2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.
Pregnancy
Pregnancy Category B: Pronervon given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested.
Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral Pronervon beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the post-partum period. The no-effect dose for these effects was 6 mg/kg, which is 3 times the MRHD on a mg/m2 basis.
There are no adequate and well-controlled studies of Pronervon in pregnant women. Pronervon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether Pronervon is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when Pronervon is administered to a nursing mother.
Pediatric Use
There are no adequate and well-controlled trials documenting the safety and efficacy of Pronervon in any illness occurring in children.
ADVERSE REACTIONS
The experience described in this section derives from studies in patients with Alzheimer's disease and vascular dementia.
Adverse Events Leading to Discontinuation: In placebo-controlled trials in which dementia patients received doses of Pronervon up to 20 mg/day, the likelihood of discontinuation because of an adverse event was the same in the Pronervon group as in the placebo group. No individual adverse event was associated with the discontinuation of treatment in 1% or more of Namenda-treated patients and at a rate greater than placebo.
Adverse Events Reported in Controlled Trials: The reported adverse events in Pronervon trials reflect experience gained under closely monitored conditions in a highly selected patient population. In actual practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior and the types of patients treated may differ. Table 1 lists treatment-emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled dementia trials and for which the rate of occurrence was greater for patients treated with Pronervon than for those treated with placebo. No adverse event occurred at a frequency of at least 5% and twice the placebo rate.
| Body System Adverse Event | Placebo (N = 922) % | Pronervon (N = 940) % |
| Body as a Whole | ||
| Fatigue | 1 | 2 |
| Pain | 1 | 3 |
| Cardiovascular System | ||
| Hypertension | 2 | 4 |
| Central and Peripheral Nervous System | ||
| Dizziness | 5 | 7 |
| Headache | 3 | 6 |
| Gastrointestinal System | ||
| Constipation | 3 | 5 |
| Vomiting | 2 | 3 |
| Musculoskeletal System | ||
| Back pain | 2 | 3 |
| Psychiatric Disorders | ||
| Confusion | 5 | 6 |
| Somnolence | 2 | 3 |
| Hallucination | 2 | 3 |
| Respiratory System | ||
| Coughing | 3 | 4 |
| Dyspnea | 1 | 2 |
Other adverse events occurring with an incidence of at least 2% in Namenda-treated patients but at a greater or equal rate on placebo were agitation, fall, inflicted injury, urinary incontinence, diarrhea, bronchitis, insomnia, urinary tract infection, influenza-like symptoms, abnormal gait, depression, upper respiratory tract infection, anxiety, peripheral edema, nausea, anorexia, and arthralgia.
The overall profile of adverse events and the incidence rates for individual adverse events in the subpopulation of patients with moderate to severe Alzheimer's disease were not different from the profile and incidence rates described above for the overall dementia population.
Vital Sign Changes: Pronervon and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, diastolic blood pressure, and weight) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. There were no clinically important changes in vital signs in patients treated with Pronervon. A comparison of supine and standing vital sign measures for Pronervon and placebo in elderly normal subjects indicated that Pronervon treatment is not associated with orthostatic changes.
Laboratory Changes: Pronervon and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with Pronervon treatment.
ECG Changes: Pronervon and placebo groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in ECG parameters associated with Pronervon treatment.
Other Adverse Events Observed During Clinical Trials
Pronervon has been administered to approximately 1350 patients with dementia, of whom more than 1200 received the maximum recommended dose of 20 mg/day. Patients received Pronervon treatment for periods of up to 884 days, with 862 patients receiving at least 24 weeks of treatment and 387 patients receiving 48 weeks or more of treatment.
Treatment emergent signs and symptoms that occurred during 8 controlled clinical trials and 4 open-label trials were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using WHO terminology, and event frequencies were calculated across all studies.
All adverse events occurring in at least two patients are included, except for those already listed in Table 1, WHO terms too general to be informative, minor symptoms or events unlikely to be drug-caused, e.g., because they are common in the study population. Events are classified by body system and listed using the following definitions: frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to Pronervon treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.
Body as a Whole: Frequent: syncope. Infrequent: hypothermia, allergic reaction.
Cardiovascular System: Frequent: cardiac failure. Infrequent: angina pectoris, bradycardia, myocardial infarction, thrombophlebitis, atrial fibrillation, hypotension, cardiac arrest, postural hypotension, pulmonary embolism, pulmonary edema.
Central and Peripheral Nervous System: Frequent: transient ischemic attack, cerebrovascular accident, vertigo, ataxia, hypokinesia. Infrequent: paresthesia, convulsions, extrapyramidal disorder, hypertonia, tremor, aphasia, hypoesthesia, abnormal coordination, hemiplegia, hyperkinesia, involuntary muscle contractions, stupor, cerebral hemorrhage, neuralgia, ptosis, neuropathy.
Gastrointestinal System: Infrequent: gastroenteritis, diverticulitis, gastrointestinal hemorrhage, melena, esophageal ulceration.
Hemic and Lymphatic Disorders: Frequent: anemia. Infrequent: leukopenia.
Metabolic and Nutritional Disorders: Frequent: increased alkaline phosphatase, decreased weight. Infrequent: dehydration, hyponatremia, aggravated diabetes mellitus.
Psychiatric Disorders: Frequent: aggressive reaction. Infrequent: delusion, personality disorder, emotional lability, nervousness, sleep disorder, libido increased, psychosis, amnesia, apathy, paranoid reaction, thinking abnormal, crying abnormal, appetite increased, paroniria, delirium, depersonalization, neurosis, suicide attempt.
Respiratory System: Frequent: pneumonia. Infrequent: apnea, asthma, hemoptysis.
Skin and Appendages: Frequent: rash. Infrequent: skin ulceration, pruritus, cellulitis, eczema, dermatitis, erythematous rash, alopecia, urticaria.
Special Senses: Frequent: cataract, conjunctivitis. Infrequent: macula lutea degeneration, decreased visual acuity, decreased hearing, tinnitus, blepharitis, blurred vision, corneal opacity, glaucoma, conjunctival hemorrhage, eye pain, retinal hemorrhage, xerophthalmia, diplopia, abnormal lacrimation, myopia, retinal detachment.
Urinary System: Frequent: frequent micturition. Infrequent: dysuria, hematuria, urinary retention.
Events Reported Subsequent to the Marketing of Pronervon, both US and Ex-US
Although no causal relationship to Pronervon treatment has been found, the following adverse events have been reported to be temporally associated with Pronervon treatment and are not described elsewhere in labeling: aspiration pneumonia, asthenia, atrioventricular block, bone fracture, carpal tunnel syndrome, cerebral infarction, chest pain, cholelithiasis, claudication, colitis, deep venous thrombosis, depressed level of consciousness (including loss of consciousness and rare reports of coma), dyskinesia, dysphagia, encephalopathy, gastritis, gastroesophageal reflux, grand mal convulsions, intracranial hemorrhage, hepatitis (including increased ALT and AST and hepatic failure), hyperglycemia, hyperlipidemia, hypoglycemia, ileus, increased INR, impotence, lethargy, malaise, myoclonus, neuroleptic malignant syndrome, acute pancreatitis, Parkinsonism, acute renal failure (including increased creatinine and renal insufficiency), prolonged QT interval, restlessness, sepsis, Stevens-Johnson syndrome, suicidal ideation, sudden death, supraventricular tachycardia, tachycardia, tardive dyskinesia, thrombocytopenia, and hallucinations (both visual and auditory).
ANIMAL TOXICOLOGY
Pronervon induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists. Lesions were seen after a single dose of Pronervon. In a study in which rats were given daily oral doses of Pronervon for 14 days, the no-effect dose for neuronal necrosis was 6 times the maximum recommended human dose on a mg/m2 basis. The potential for induction of central neuronal vacuolation and necrosis by NMDA receptor antagonists in humans is unknown.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Pronervon HCl is not a controlled substance.
Physical and Psychological Dependence: Pronervon HCl is a low to moderate affinity uncompetitive NMDA antagonist that did not produce any evidence of drug-seeking behavior or withdrawal symptoms upon discontinuation in 2,504 patients who participated in clinical trials at therapeutic doses. Post marketing data, outside the U.S., retrospectively collected, has provided no evidence of drug abuse or dependence.
OVERDOSAGE
Signs and symptoms associated with Pronervon overdosage in clinical trials and from worldwide marketing experience include agitation, confusion, ECG changes, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of Pronervon worldwide was 2.0 grams in a patient who took Pronervon in conjunction with unspecified antidiabetic medications. The patient experienced coma, diplopia, and agitation, but subsequently recovered.
Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug.
As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of Pronervon can be enhanced by acidification of urine.
DOSAGE AND ADMINISTRATION
The dosage of Pronervon shown to be effective in controlled clinical trials is 20 mg/day.
The recommended starting dose of Pronervon is 5 mg once daily. The recommended target dose is 20 mg/day. The dose should be increased in 5 mg increments to 10 mg/day (5 mg twice a day), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice a day). The minimum recommended interval between dose increases is one week.
Pronervon can be taken with or without food.
Patients/caregivers should be instructed on how to use the Pronervon Oral Solution dosing device. They should be made aware of the patient instruction sheet that is enclosed with the product. Patients/caregivers should be instructed to address any questions on the usage of the solution to their physician or pharmacist.
Doses in Special Populations
A target dose of 5 mg BID is recommended in patients with severe renal impairment (creatinine clearance of 5 – 29 mL/min based on the Cockroft-Gault equation):
For males: CLcr = [140-age (years)] · Weight (kg)/[72 · serum creatinine (mg/dL)]
For females: CLcr = 0.85 · [140-age (years)] · Weight (kg)/[72 · serum creatinine (mg/dL)]
HOW SUPPLIED
5 mg Tablet:
Bottle of 60 NDC #0456-3205-60
10 x 10 Unit Dose NDC #0456-3205-63
The capsule-shaped, film-coated tablets are tan, with the strength (5) debossed on one side and FL on the other.
10 mg Tablet:
Bottle of 60 NDC #0456-3210-60
10 x 10 Unit Dose NDC #0456-3210-63
The capsule-shaped, film-coated tablets are gray, with the strength (10) debossed on one side and FL on the other.
Titration Pak:
PVC/Aluminum Blister package containing 49 tablets. 28 x 5 mg and 21 x 10 mg tablets.
NDC #0456-3200-14
The 5 mg capsule-shaped, film-coated tablets are tan, with the strength (5) debossed on one side and FL on the other. The 10 mg capsule-shaped, film-coated tablets are gray, with the strength (10) debossed on one side and FL on the other.
Oral Solution:
The dosage recommendations for oral solution are the same as those for tablets. The oral solution is clear, alcohol-free, sugar-free, and peppermint flavored.
2 mg/mL Oral Solution (10 mg = 5 mL)
12 fl. oz. (360 mL) bottle NDC #0456-3202-12
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045
Licensed from Merz Pharmaceuticals GmbH
Rev. January 2011
© 2007 Forest Laboratories, Inc.
PATIENT INSTRUCTIONS FOR Pronervon® Oral Solution
Follow the directions below to use your Pronervon® Oral Solution dosing device.
IMPORTANT: Read these instructions before using Pronervon ® Oral Solution.
| 1. Remove oral dosing syringe along with the green cap and plastic tube from its protective plastic bag. Attach the tube to the green cap if it isn't already attached. | ||
| 2. The bottle comes with a child-resistant cap. Open it by pushing down on the cap while turning the cap counter-clockwise (to the left). Remove the unscrewed cap. Carefully remove the seal from the bottle and discard. | ||
| 3. Insert the plastic tube fully into the bottle and screw the green cap tightly onto the bottle by turning the cap clockwise (to the right). | ||
| 4. The green cap has an attached lid which is to be used for sealing the product in between doses. Keeping the bottle upright on the table, remove the lid to uncover the opening on the top of the cap. With the plunger fully depressed, insert the tip of syringe firmly into the opening in the cap. | ||
| 5. While holding the syringe, gently pull the plunger of the syringe up to draw medicine into the syringe. | ||
| 6. Remove the syringe from the opening of the cap. Invert the syringe (point tip upwards) and slowly press the plunger to a level that pushes out any large air bubbles that may be present. Keep the plunger in this position. Do not worry about a few tiny bubbles. This will not affect your dose in any way. | ||
| 7. Re-insert the tip of the syringe into the opening of the cap. While holding the syringe, continue to gently pull out the plunger until the bottom of the black ring of the plunger reaches the appropriate mark on the syringe that corresponds to the dose prescribed. | ||
| 8. Remove the syringe from the bottle and swallow the Oral Solution directly from the syringe. Do not mix with any other liquid. | ||
| 9. After use, reseal the bottle by snapping the attached lid closed. | ||
| 10. Rinse the empty syringe by inserting the open end of the syringe into a glass of water, pulling the plunger out to draw in water, and pushing the plunger in to remove the water. Repeat several times. Allow the syringe to air dry. |
Pronervon pharmaceutical active ingredients containing related brand and generic drugs:
Pronervon available forms, composition, doses:
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.