Pharmaceutical Approval Update
Rivastigmine Transdermal System (Exelon Patch)
Manufacturer: Novartis Pharmaceuticals Corp, East Hanover, NJ
Indication: The rivastigmine transdermal system is indicated for the treatment of mild-to-moderate dementia of the Alzheimer’s type and for mild-to-moderate dementia associated with Parkinson’s disease (PD). The dementia of PD is characterized by impairments in executive function, memory retrieval, and attention.
Drug Class: Rivastigmine is a reversible cholinesterase inhibitor and is known chemically as (S)- 3-[1-(dimethylamino) ethyljphenyl ethylmethylcarbamate.
Uniqueness of Drug: This new therapy is the first trans-dermal therapy for Alzheimer’s disease, a degenerative condition that affects millions of people in the U.S. Placebo-controlled clinical trials showed significant benefits to patients in terms of their memory and overall functioning. canadian pharmacy cialis
The patch maintains steady drug levels in the bloodstream, improving tolerability and allowing a higher proportion of patients to receive therapeutic doses, compared with the capsule formulation. The transdermal system is applied to the back, chest, or upper arm, and it provides smooth, continuous delivery of medication through the skin over a period of 24 hours.
Warnings and Precautions:
Gastrointestinal adverse reactions: At higher-than-recommended doses, the patch is associated with significant gastrointestinal (GI) adverse reactions, including nausea, vomiting, diarrhea, anorexia or decreased appetite, and weight loss. For this reason, the starting dose should always be 4.6 mg per 24 hours. This dose should be titrated to the maintenance dose of 9.5 mg per 24 hours.
If treatment is interrupted for more than several days, the medication should be reinitiated with the lowest daily dose to reduce the possibility of severe vomiting and its potentially serious sequelae. In one postmarketing report, severe vomiting with esophageal rupture followed inappropriate reinitiation of treatment with a 4.5-mg dose of an oral formulation after eight weeks of interrupted treatment.
At higher-than-recommended doses, caregivers should be advised of the elevated incidence of nausea and vomiting associated with the patch as well as the possibility of anorexia and weight loss. Caregivers should be encouraged to monitor patients for these adverse events and should inform the physician if they occur. It is critical to inform caregivers that if therapy has been interrupted for more than several days, the next dose should not be administered until the physician has been consulted. Nausea and vomiting: In the controlled clinical trial, the following patients experienced nausea: 7% of patients treated with the rivastigmine transdermal system at a dose of 9.5 mg over a 24-hour period, 23% of patients who received the rivastigmine capsule at doses up to 6 mg twice daily, and 5% of those who received placebo. In the same trial, 6% of patients treated with the patch at this dosage experienced vomiting, compared with 17% of patients who received the capsule at doses up to 6 mg twice daily and with 3% of those who received placebo. viagra soft
The proportion of patients who discontinued treatment because of vomiting was 0% of patients given the patch at a dosage of 9.5 mg per 24 hours, 2% of patients who received the capsule at doses up to 6 mg twice daily, and 0% of those who received placebo. Vomiting was severe in none of the patients who received the patch 9.5 mg per 24 hours, in 1% of patients who received the capsule at doses up to 6 mg twice daily, and in none of those who received placebo.
In the same trial, 21% of patients using the higher dose of the patch at 17.4 mg per 24 hours experienced nausea and 19% experienced vomiting. The proportion of these patients who discontinued treatment as a result of vomiting was 2%. Vomiting was severe in 1% of patients wearing the patch at a dosage of 17.4 mg per 24 hours.
Weight loss: In the controlled clinical trial, the following patients had a weight loss equal to or greater than 7% of their baseline weight: 8% of those treated with the patch at a dosage of 9.5 mg per 24 hours, 11% of patients who received the riva-stigmine capsule at doses up to 6 mg twice daily, and 6% of those who received placebo. In the same trial, 12% of those treated with 17.4 mg per 24 hours had weight loss equal to or greater than 7% of their baseline weight. It is not clear how much of the weight loss was related to the anorexia, nausea, vomiting, and diarrhea associated with the drug.
Diarrhea: In the controlled clinical trial, 6% of patients treated with the patch at a dosage of 9.5 mg per 24 hours developed diarrhea, compared with 5% of patients who received the rivastigmine capsule at doses up to 6 mg twice daily, 10% of those treated with 17.4 mg per 24 hours, and 3% of those who received placebo.
Anorexia and decreased appetite: In the controlled clinical trial, 3% of patients treated with the patch at a dose of 9.5 mg/24 hours experienced decreased appetite or anorexia, compared with 9% of patients who were receiving the capsule at doses up to 6 mg twice daily, 9% of those using the patch at a dose of 17.4 mg per 24 hours, and 2% of those receiving placebo.
Peptic ulcers and GI bleeding: Because of their pharmacological action, cholinesterase inhibitors may be expected to increase gastric acid secretion caused by increased cholin-ergic activity. Therefore, patients should be monitored closely for symptoms of active or occult GI bleeding, especially if they are at an increased risk for developing ulcers (e.g., patients with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs [NSAIDsj). Clinical studies of rivastigmine have shown no significant increase, relative to placebo, in the incidence of either peptic ulcer disease or GI bleeding.
Anesthesia: As a cholinesterase inhibitor, rivastigmine is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
Cardiovascular Conditions: Drugs that increase cholin-ergic activity may have vagotonic effects on the heart rate, such as bradycardia. The potential for this action may be particularly important to patients with sick sinus syndrome or other supraventricular cardiac conduction conditions. In clinical trials, rivastigmine was not associated with an increased incidence of cardiovascular adverse events, changes in heart rate or blood pressure, or electrocardiographic abnormalities.
Genitourinary Conditions: Although a genitourinary effect was not observed in clinical trials of rivastigmine capsules, drugs that increase cholinergic activity may cause urinary obstruction. pharmacy united kingdom
Seizures. Drugs that increase cholinergic activity are believed to have a potential for causing seizures. However, seizure activity may also be a manifestation of Alzheimer’s disease.
Extrapyramidal symptoms: Like other cholinomimetic agents, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening of parkinsonian symptoms, particularly tremor, has been observed in patients with dementia associated with PD who received rivastigmine capsules.
Pulmonary Conditions: Like other drugs that increase cholinergic activity, rivastigmine should be used with care in patients with a history of asthma or obstructive pulmonary diseas e.
Driving and Using Machines: Dementia may cause gradual impairment of driving performance or may compromise the ability to use machinery. The administration of rivastigmine may also result in adverse events that are detrimental to these functions. Thus, the ability to continue driving or operating machinery should be routinely evaluated by the treating physician.
Dosage and Administration:
Initial dose: Treatment is started with the rivastigmine transdermal system at a dosage of 4.6 mg per 24 hours. After a minimum of four weeks of treatment and if this dose is well tolerated, it should be increased to 9.5 mg per 24 hours, the recommended effective dose. Apcalis Oral Jelly
Maintenance dose: Dose increases should occur only after a minimum of four weeks at the previous dose if the previous dose has been well tolerated. The maximum recommended dose is 9.5 mg per 24 hours. Higher doses confer no appreciable additional benefit and are associated with a significant increased incidence of adverse events. If these adverse effects (e.g., nausea, vomiting, diarrhea, loss of appetite) cause intolerance during treatment, patients should be instructed to discontinue treatment for several days and then to restart therapy at the same or next lower dose level. If treatment is interrupted for longer than several days, the medication should be reinitiated with the lowest daily dose and titrated as described previously.
Switching from capsules or an oral solution: Patients taking capsules or the oral solution may be switched to the patch as follows:
- Patients receiving a total daily dose of less than 6 mg of oral rivastigmine can be switched to the patch at a dosage of 4.6 mg per 24 hours.
- Patients receiving a total daily dose of 6 to 12 mg of oral rivastigmine may be directly switched to the patch at a dosage of 9.5 mg per 24 hours.
General Recommendations: Each patch is a thin, matrix-type transdermal system consisting of three layers when it is worn. A fourth layer, the release liner, covers the adhesive layer prior to use and is removed when the patch is applied to the skin.
The patch should first be applied on the day following the last oral administration. It is applied once a day to clean, dry, hairless, intact healthy skin in an area that is not in contact with tight clothing. The upper or lower back is recommended as the site of application, because patients are less likely to remove the patch when it is in this location. When sites on the back are not accessible, the patch can be applied to the upper arm or chest.
The patch should not be applied to skin that is red, irritated, or cut. The application site should be changed daily to avoid potential irritation, although consecutive patches can be applied to the same anatomic site (e.g., another spot on the upper back). The patch should be pressed down firmly until the edges stick well. Patients can wear the patch while bathing and in hot weather.
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The patch should be replaced with a new one every 24 hours, but patients should not apply the new patch to the same spot for at least 14 days. Patients and caregivers should be instructed accordingly.
Commentary: The Exelon patch represents an innovative way to deliver what is now standard therapy for mild-to-moderate Alzheimer’s disease through a skin patch instead of an oral capsule. The patch maintains steady drug concentrations in the bloodstream, improving tolerability and allowing more patients to receive therapeutic doses, compared with the capsule. When applied to the back, chest, or upper arm, the patch provides smooth, continuous drug delivery for 24 hours.
GI side effects are commonly seen with the class of drugs called cholinesterase inhibitors. The recommended dose of the patch greatly reduces these side effects, with three times fewer reports of nausea and vomiting than with the capsule formulation.