Lametta

Lametta may be available in the countries listed below.

Ingredient matches for Lametta

Letrozole

Letrozole is reported as an ingredient of Lametta in the following countries:

• Poland

International Drug Name Search

Reactine

Reactine may be available in the countries listed below.

Ingredient matches for Reactine

Cetirizine

Cetirizine dihydrochloride (a derivative of Cetirizine) is reported as an ingredient of Reactine in the following countries:

• Belgium


• Canada


• Czech Republic


• Germany


• Luxembourg


• Mexico


• Netherlands


• Norway


• Poland


• Slovakia


• Spain

Pseudoephedrine

Pseudoephedrine hydrochloride (a derivative of Pseudoephedrine) is reported as an ingredient of Reactine in the following countries:

• Belgium


• Canada


• Germany

International Drug Name Search

Ropinirole

Generic Name: Ropinirole hydrochloride

Dosage Form: tablet

Ropinirole Description

Ropinirole hydrochloride is an orally administered non-ergoline dopamine agonist. It is the hydrochloride salt of 4-[2-(dipropylamino)-ethyl]-1,3-dihydro-2H-indol-2-one and has an molecular formula of C16H24N2O•HCl. The molecular weight is 296.84 (260.38 as the free base).

The structural formula is:

Ropinirole hydrochloride, USP is a white to cream colored crystalline powder with a melting range of 241° to 245°C and a solubility of 133 mg/mL in water.

Each tablet contains Ropinirole hydrochloride equivalent to Ropinirole, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg. Inactive ingredients consist of: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. In addition, the following product specific coloring agents are employed:

0.5 mg -	D&C Yellow No. 10 Aluminum Lake
1 mg -	D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake
2 mg -	D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake
3 mg -	D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake
4 mg -	D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake
5 mg -	D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake

Ropinirole Tablets USP, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg and 5 mg Meets USP Dissolution Test 2.

Ropinirole - Clinical Pharmacology

Mechanism of Action

Ropinirole is a non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 and D3 dopamine receptor subtypes, binding with higher affinity to D3 than to D2 or D4 receptor subtypes. Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D1, 5-HT1, 5-HT2, benzodiazepine, GABA, muscarinic, alpha1-, alpha2-, and beta-adrenoreceptors.

Parkinson's Disease

The precise mechanism of action of Ropinirole hydrochloride as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of postsynaptic dopamine D2-type receptors within the caudate-putamen in the brain. This conclusion is supported by studies that show that Ropinirole improves motor function in various animal models of Parkinson's disease. In particular, Ropinirole attenuates the motor deficits induced by lesioning the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates. The relevance of D3 receptor binding in Parkinson's disease is unknown.

Restless Legs Syndrome (RLS)

The precise mechanism of action of Ropinirole hydrochloride as a treatment for Restless Legs Syndrome (also known as Ekbom Syndrome) is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS.

Clinical Pharmacology Studies

In healthy normotensive subjects, single oral doses of Ropinirole hydrochloride in the range 0.01 mg to 2.5 mg had little or no effect on supine blood pressure and pulse rates. Upon standing, Ropinirole hydrochloride caused decreases in systolic and diastolic blood pressure at doses above 0.25 mg. In some subjects, these changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case, transient sinus arrest with syncope. With repeat dosing and slow titration up to 4 mg once daily in healthy volunteers, postural hypotension or hypotension-related adverse events were noted in 13% of subjects on Ropinirole hydrochloride and none of the subjects on placebo.

The mechanism of postural hypotension induced by Ropinirole hydrochloride is presumed to be due to a D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Nausea is a common concomitant symptom of orthostatic signs and symptoms.

At oral doses as low as 0.2 mg, Ropinirole hydrochloride suppressed serum prolactin concentrations in healthy male volunteers.

Ropinirole hydrochloride had no dose related effect on ECG wave form and rhythm in young, healthy, male volunteers in the range of 0.01 mg to 2.5 mg.

Ropinirole hydrochloride had no dose- or exposure-related effect on mean QT intervals in healthy male and female volunteers titrated to doses up to 4 mg/day. The effect of Ropinirole hydrochloride on QT intervals at higher exposures achieved either due to drug interactions or at doses used in Parkinson's disease has not been systematically evaluated.

Pharmacokinetics

Absorption, Distribution, Metabolism, and Elimination

The pharmacokinetics of Ropinirole are similar in Parkinson's disease patients and patients with Restless Legs Syndrome. Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1 to 2 hours. In clinical studies, over 88% of a radiolabeled dose was recovered in urine and the absolute bioavailability was 55%, indicating a first-pass effect. Relative bioavailability from a tablet compared to an oral solution is 85%. Food does not affect the extent of absorption of Ropinirole, although its Tmax is increased by 2.5 hours and its Cmax is decreased by approximately 25% when the drug is taken with a high-fat meal. The clearance of Ropinirole after oral administration to patients is 47 L/hr (cv = 45%) and its elimination half-life is approximately 6 hours. Ropinirole is extensively metabolized by the liver to inactive metabolites and displays linear kinetics over the therapeutic dosing range of 1 mg to 8 mg 3 times daily. Steady-state concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing is predictive from single dosing.

Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg (cv = 32%). It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1.

The major metabolic pathways are N-despropylation and hydroxylation to form the inactive N-despropyl and hydroxy metabolites. In vitro studies indicate that the major cytochrome P450 isozyme involved in the metabolism of Ropinirole is CYP1A2, an enzyme known to be stimulated by smoking and omeprazole, and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones such as ciprofloxacin and norfloxacin. The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites. The hydroxy metabolite of Ropinirole is rapidly glucuronidated. Less than 10% of the administered dose is excreted as unchanged drug in urine. N-despropyl Ropinirole is the predominant metabolite found in urine (40%), followed by the carboxylic acid metabolite (10%), and the glucuronide of the hydroxy metabolite (10%).

P450 Interaction

In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of Ropinirole. Inhibitors or inducers of this enzyme have been shown to alter its clearance when coadministered with Ropinirole. Therefore, if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with Ropinirole hydrochloride, adjustment of the dose of Ropinirole hydrochloride may be required.

Population Subgroups

Because therapy with Ropinirole hydrochloride is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary.

Age

Oral clearance of Ropinirole is reduced by 30% in patients above 65 years of age compared to younger patients. Dosage adjustment is not necessary in the elderly (above 65 years), as the dose of Ropinirole is to be individually titrated to clinical response.

Gender

Female and male patients showed similar oral clearance.

Race

The influence of race on the pharmacokinetics of Ropinirole has not been evaluated.

Cigarette Smoking

Smoking is expected to increase the clearance of Ropinirole since CYP1A2 is known to be induced by smoking. In a study in patients with RLS, smokers (n = 7) had an approximate 30% lower Cmax and a 38% lower AUC than did nonsmokers (n = 11), when those parameters were normalized for dose.

Renal Impairment

Based on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of Ropinirole in patients with moderate renal impairment (creatinine clearance between 30 to 50 mL/min) compared to an age-matched population with creatinine clearance above 50 mL/min. Therefore, no dosage adjustment is necessary in moderately renally impaired patients. The use of Ropinirole hydrochloride in patients with severe renal impairment has not been studied.

The effect of hemodialysis on drug removal is not known, but because of the relatively high apparent volume of distribution of Ropinirole (525 L), the removal of the drug by hemodialysis is unlikely.

Hepatic Impairment

The pharmacokinetics of Ropinirole have not been studied in hepatically impaired patients. These patients may have higher plasma levels and lower clearance of the drug than patients with normal hepatic function. The drug should be titrated with caution in this population.

Other Diseases

Population pharmacokinetic analysis revealed no change in the oral clearance of Ropinirole in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and insomnia compared to patients with Parkinson's disease only.

Clinical Trials

Parkinson's Disease

The effectiveness of Ropinirole hydrochloride in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of 11 randomized, controlled trials. Four were conducted in patients with early Parkinson’s disease and no concomitant levodopa (L-dopa), and seven were conducted in patients with advanced Parkinson’s disease with concomitant L-dopa.

Among these 11 studies, three placebo-controlled studies provide the most persuasive evidence of Ropinirole's effectiveness in the management of patients with Parkinson's disease who were and were not receiving concomitant L-dopa. Two of these three trials enrolled patients with early Parkinson's disease (without L-dopa) and one enrolled patients receiving L-dopa.

In these studies a variety of measures were used to assess the effects of treatment (e.g., the Unified Parkinson's Disease Rating Scale [UPDRS], Clinical Global Impression [CGI] scores, patient diaries recording time "on" and "off," and tolerability of L-dopa dose reductions).

In both studies of early Parkinson's disease (without L-dopa) patients, the motor component (Part III) of the UPDRS was the primary outcome assessment. The UPDRS is a 4-part multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV). Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.) scored for different body regions and has a maximum (worst) score of 108. Responders were defined as patients with at least a 30% reduction in the Part III score.

In the study of advanced Parkinson's disease (with L-dopa) patients, both reduction in percent awake time spent "off" and the ability to reduce the daily use of L-dopa were assessed as a combined endpoint and individually.

Studies in Patients With Early Parkinson's Disease (Without L-dopa)

One early therapy study was a 12-week multicenter study in which 63 patients (41 on Ropinirole hydrochloride) with idiopathic Parkinson's disease receiving concomitant anti-Parkinson medication (but not L-dopa) were randomized to either Ropinirole hydrochloride or placebo. Patients had a mean disease duration of approximately 2 years. Patients were eligible for enrollment if they presented with bradykinesia and at least tremor, rigidity, or postural instability. In addition, they must have been classified as Hoehn & Yahr Stage I-IV. This scale, ranging from I = unilateral involvement with minimal impairment to V = confined to wheelchair or bed, is a standard instrument used for staging patients with Parkinson's disease. The primary outcome measure in this trial was the proportion of patients experiencing a decrease (compared to baseline) of at least 30% in the UPDRS motor score.

Patients were titrated for up to 10 weeks, starting at 0.5 mg twice daily, with weekly increments of 0.5 mg twice daily to a maximum of 5 mg twice daily. Once patients reached their maximally tolerated dose (or 5 mg twice daily), they were maintained on that dose through 12 weeks. The mean dose achieved by patients at study endpoint was 7.4 mg/day. At the end of 12 weeks, 71% of patients treated with Ropinirole hydrochloride were responders, compared with 41% of patients in the placebo group (p = 0.021).

Statistically significant differences between the percentage of responders on Ropinirole hydrochloride compared to placebo were seen after 8 weeks of treatment.

In addition, the mean percentage improvement from baseline in the Total Motor Score was 43% in patients treated with Ropinirole hydrochloride compared with 21% in patients treated with placebo (p = 0.018).

Statistically significant differences in UPDRS motor score between Ropinirole hydrochloride and placebo were seen after 2 weeks of treatment.

The median daily dose at which a 30% reduction in UPDRS motor score was sustained was 4 mg.

The second trial in early Parkinson's disease (without L-dopa) patients was a double-blind, randomized, placebo-controlled, 6-month study. Patients were essentially similar to those in the study described above; concomitant use of selegiline was allowed, but patients were not permitted to use anticholinergics or amantadine during the study. Patients had a mean disease duration of 2 years and limited (not more than a 6-week period) or no prior exposure to L-dopa. The starting dose of Ropinirole hydrochloride in this trial was 0.25 mg 3 times daily. The dose was titrated at weekly intervals by increments of 0.25 mg 3 times daily to a dose of 1 mg 3 times daily. Further titrations at weekly intervals were at increments of 0.5 mg 3 times daily up to a dose of 3 mg 3 times daily, and then weekly at increments of 1 mg 3 times daily. Patients were to be titrated to a dose of at least 1.5 mg 3 times daily and then to their maximally tolerated dose, up to a maximum of 8 mg 3 times daily. The mean dose attained in patients at study endpoint was 15.7 mg/day.

The primary measure of effectiveness was the mean percent reduction (improvement) from baseline in the UPDRS Motor Score. In this study 241 patients were enrolled. At the end of the 6-month study, patients treated with Ropinirole hydrochloride had 22% improvement in motor score, compared with a 4% worsening in the placebo group (p < 0.001).

Statistically significant differences in UPDRS motor score improvement between Ropinirole hydrochloride and placebo were seen after 12 weeks of treatment.

Study in Patients With Advanced Parkinson's Disease (With L-dopa)

This double-blind, randomized, placebo-controlled, 6-month trial evaluated 148 patients (Hoehn & Yahr II-IV) who were not adequately controlled on L-dopa. Patients in this study had a mean disease duration of approximately 9 years, had been exposed to levodopa for approximately 7 years, and had experienced "on-off" periods with L-dopa therapy. Patients previously receiving stable doses of selegiline, amantadine, and/or anticholinergic agents could continue on these agents during the study. Patients were started at a dose of 0.25 mg 3 times daily of Ropinirole hydrochloride and titrated upward by weekly intervals until an optimal therapeutic response was achieved. The maximum dose of study medication was 8 mg 3 times daily. All patients had to be titrated to at least a dose of 2.5 mg 3 times daily. Patients could then be maintained on this dose level or higher for the remainder of the study. Once a dose of 2.5 mg 3 times daily was achieved, patients underwent a mandatory reduction in their L-dopa dose, to be followed by additional mandatory reductions with continued escalation of the dose of Ropinirole hydrochloride. Reductions in the dosage of L-dopa were also allowed if patients experienced adverse events that the investigator considered related to dopaminergic therapy. The mean dose attained at study endpoint was 16.3 mg/day. The primary outcome was the proportion of responders, defined as patients who were able both to achieve a decrease (compared to baseline) of at least 20% in their L-dopa dose and a decrease of at least 20% in the proportion of the time awake in the "off" condition (a period of time during the day when patients are particularly immobile), as determined by patient diary. In addition, the mean percent change from baseline in daily L-dopa dose was examined.

At the end of 6 months, 28% of patients treated with Ropinirole hydrochloride were classified as responders (based on combined endpoint) while 11% of patients treated with placebo were responders (p = 0.02). Based on the protocol-mandated reductions in L-dopa dosage with escalating doses of Ropinirole hydrochloride, patients treated with Ropinirole hydrochloride had a 19.4% mean reduction in L-dopa dose while patients treated with placebo had a 3% reduction (p < 0.001). L-dopa dosage reduction was also allowed during the study if dyskinesias or other dopaminergic effects occurred. Overall, reduction of L-dopa dose was sustained in 87% of patients treated with Ropinirole hydrochloride and in 57% of patients on placebo. On average, the L-dopa dose was reduced by 31% in patients treated with Ropinirole hydrochloride.

The mean number of "off" hours per day during baseline was 6.4 hours for patients treated with Ropinirole hydrochloride and 7.3 hours for patients treated with placebo. At the end of the 6-month study, patients treated with Ropinirole hydrochloride had a mean of 4.9 hours per day of "off" time, while placebo-treated patients had a mean of 6.4 hours per day of "off" time.

Restless Legs Syndrome (RLS)

The effectiveness of Ropinirole hydrochloride in the treatment of RLS was demonstrated in randomized, double-blind, placebo-controlled studies in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria (see INDICATIONS AND USAGE). Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of ≥15 on the International RLS Rating Scale (IRLS scale) at baseline. Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, and anemia) were excluded. All studies employed flexible dosing, with patients initiating therapy at 0.25 mg Ropinirole hydrochloride once daily. Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily. All doses were taken between 1 and 3 hours before bedtime.

A variety of measures were used to assess the effects of treatment, including the IRLS Scale and Clinical Global Impression-Global Improvement (CGI-I) scores. The IRLS Scale contains ten items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. Three of the controlled studies utilized the change from baseline in the IRLS Scale at the week 12 endpoint as the primary efficacy outcome.

Three hundred eighty patients were randomized to receive Ropinirole hydrochloride (n = 187) or placebo (n = 193) in a U.S. study; 284 were randomized to receive either Ropinirole hydrochloride (n = 146) or placebo (n = 138) in a multinational study (excluding U.S.); and 267 patients were randomized to Ropinirole hydrochloride (n = 131) or placebo (n = 136) in a multinational study (including U.S.). Across the three studies, the mean duration of RLS was 16 to 22 years (range of 0 to 65 years), mean age was approximately 54 years (range of 18 to 79 years), and approximately 61% were women. The mean dose at week 12 was approximately 2 mg/day for the three studies.

In all three studies, a statistically significant difference between the treatment group receiving Ropinirole hydrochloride and the treatment group receiving placebo was observed at week 12 for both the mean change from baseline in the IRLS Scale total score and the percentage of patients rated as responders (much improved or very much improved) on the CGI-I (see Table 1).

Table 1. Mean Change in IRLS Score and Percent Responders on CGI-I

	Ropinirole	Placebo	p-value
Mean Change in IRLS score at Week 12
U.S. study	-13.5	-9.8	p < 0.0001
Multinational study (excluding U.S.)	-11	-8	p = 0.0036
Multinational study (including U.S.)	-11.2	-8.7	p = 0.0197
Percent responders on CGI-I at Week 12
U.S. study	73.3%	56.5%	p = 0.0006
Multinational study (excluding U.S.)	53.4%	40.9%	p = 0.0416
Multinational study (including U.S.)	59.5%	39.6%	p = 0.0010

Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36-week study. Following a 24-week single-blind treatment phase (flexible doses of Ropinirole hydrochloride of 0.25 mg to 4 mg once daily), patients who were responders (defined as a decrease of > 6 points on the IRLS Scale total score relative to baseline) were randomized in double-blind fashion to placebo or continuation of Ropinirole hydrochloride for an additional 12 weeks. Relapse was defined as an increase of at least six points on the IRLS Scale total score to a total score of at least 15, or withdrawal due to lack of efficacy. For patients who were responders at week 24, the mean dose of Ropinirole was 2 mg (range 0.25 mg to 4 mg). Patients continued on Ropinirole hydrochloride demonstrated a significantly lower relapse rate compared with patients randomized to placebo (32.6% vs. 57.8%, p = 0.0156).

Indications and Usage for Ropinirole

Parkinson's Disease

Ropinirole tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease.

The effectiveness of Ropinirole tablets was demonstrated in randomized, controlled trials in patients with early Parkinson's disease who were not receiving concomitant L-dopa therapy as well as in patients with advanced disease on concomitant L-dopa (see CLINICAL PHARMACOLOGY: Clinical Trials).

Restless Legs Syndrome

Ropinirole tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).

Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations; symptoms begin or worsen during periods of rest or inactivity such as lying or sitting; symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues; and symptoms are worse or occur only in the evening or night. Difficulty falling asleep may frequently be associated with moderate-to-severe RLS.

Contraindications

Ropinirole tablets are contraindicated for patients known to have hypersensitivity to the product.

Warnings

Falling Asleep During Activities of Daily Living

Patients treated with Ropinirole hydrochloride have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on Ropinirole, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment.

In controlled clinical trials, somnolence was a common occurrence in patients receiving Ropinirole hydrochloride and is more frequent in Parkinson's disease (up to 40% Ropinirole hydrochloride, 6% placebo) than in Restless Legs Syndrome (12% Ropinirole hydrochloride, 6% placebo). Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with Ropinirole hydrochloride, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with Ropinirole hydrochloride such as concomitant sedating medications, the presence of sleep disorders (other than Restless Legs Syndrome), and concomitant medications that increase Ropinirole plasma levels (e.g., ciprofloxacin: see PRECAUTIONS: Drug Interactions). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Ropinirole hydrochloride should ordinarily be discontinued. (See DOSAGE AND ADMINISTRATION for guidance in discontinuing Ropinirole hydrochloride.) If a decision is made to continue Ropinirole hydrochloride, patients should be advised to not drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Syncope

Syncope, sometimes associated with bradycardia, was observed in association with Ropinirole hydrochloride in both Parkinson’s disease patients and RLS patients. In the two double-blind, placebo-controlled studies of Ropinirole hydrochloride in patients with Parkinson’s disease who were not being treated with L-dopa, 11.5% (18 of 157) of patients on Ropinirole hydrochloride had syncope compared to 1.4% (2 of 147) of patients on placebo. Most of these cases occurred more than 4 weeks after initiation of therapy with Ropinirole hydrochloride, and were usually associated with a recent increase in dose.

Of 208 patients being treated with both L-dopa and Ropinirole hydrochloride in placebo-controlled advanced Parkinson's disease trials, there were reports of syncope in 6 (2.9%) compared to 2 of 120 (1.7%) of placebo/ L-dopa patients.

In patients with RLS, of 496 patients treated with Ropinirole hydrochloride in 12-week placebo-controlled trials, there were reports of syncope in 5 (1%) compared with 1 of 500 (0.2%) patients treated with placebo.

Because the studies of Ropinirole hydrochloride excluded patients with significant cardiovascular disease, it is not known to what extent the estimated incidence figures apply to either Parkinson's disease or RLS patients in clinical practice. Therefore, patients with severe cardiovascular disease should be treated with caution.

Two of 47 Parkinson's disease patient volunteers enrolled in phase 1 studies had syncope following a 1 mg dose. In two studies in RLS patients that used a forced titration regimen and orthostatic challenge with intensive blood pressure monitoring, 1 of 55 RLS patients treated with Ropinirole hydrochloride compared with 0 of 27 patients receiving placebo reported syncope. In phase 1 studies including 110 healthy volunteers, one patient developed hypotension, bradycardia, and sinus arrest of 26 seconds accompanied by syncope; the patient recovered spontaneously without intervention. One other healthy volunteer reported syncope.

Symptomatic Hypotension

Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting postural hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to a postural challenge. For these reasons, Parkinson's patients being treated with dopaminergic agonists ordinarily (1) require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and (2) should be informed of this risk (see PRECAUTIONS: Information for Patients).

Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of postural hypotension in early Parkinson's disease (without L-dopa) in patients treated with Ropinirole hydrochloride. Most of these cases occurred more than 4 weeks after initiation of therapy with Ropinirole hydrochloride and were usually associated with a recent increase in dose.

In 12-week placebo-controlled trials of patients with RLS, the adverse event orthostatic hypotension was reported by 4 of 496 patients (0.8%) treated with Ropinirole hydrochloride compared with 2 of 500 patients (0.4%) receiving placebo.

In two phase 2 studies in patients with RLS that used a forced-titration regimen and orthostatic challenges with intensive blood pressure monitoring, 14 of 55 patients (25%) receiving Ropinirole hydrochloride experienced an adverse event of hypotension or postural hypotension. As described above, one additional patient was noted to have an episode of vasovagal syncope (although no blood pressure recording was documented). None of the 27 patients receiving placebo had a similar adverse event. In these studies, 11 of the 55 patients (20%) receiving Ropinirole hydrochloride and 3 of the 26 patients (12%) who had post-dose blood pressure assessments following placebo, experienced an orthostatic blood pressure decrease of at least 40 mm Hg systolic and/or at least 20 mm Hg diastolic; not all of these changes were associated with clinical symptoms. Except for its forced nature these studies used a similar titration schedule as those in the phase 3 efficacy trials.

In phase 1 studies of Ropinirole hydrochloride that included 110 healthy volunteers, nine subjects had documented symptomatic postural hypotension. These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for either Parkinson's disease patients or RLS patients. In 8 of these 9 individuals, the hypotension was accompanied by bradycardia, but did not develop into syncope (see Syncope subsection). None of these events resulted in death or hospitalization.

One of 47 Parkinson's disease patient volunteers enrolled in phase 1 studies had documented hypotension following a 2 mg dose on two occasions.

Hallucinations

In double-blind, placebo-controlled, early-therapy studies in patients with Parkinson's disease who were not treated with L-dopa, 5.2% (8 of 157) of patients treated with Ropinirole hydrochloride reported hallucinations, compared to 1.4% of patients on placebo (2 of 147). Among those patients receiving both Ropinirole hydrochloride and L-dopa in advanced Parkinson's disease (with L-dopa) studies, 10.1% (21 of 208) were reported to experience hallucinations, compared to 4.2% (5 of 120) of patients treated with placebo and L-dopa.

Hallucinations were of sufficient severity to cause discontinuation of treatment in 1.3% of the early Parkinson's disease (without L-dopa) patients and 1.9% of the advanced Parkinson's disease (with L-dopa) patients, compared to 0% and 1.7% of placebo patients, respectively.

In patients with RLS, hallucinations were reported by 0% of patients treated with Ropinirole hydrochloride (0 of 496) compared with 0.2% of patients who received placebo (1 of 500) in the 12-week placebo-controlled trials; in premarketing long-term open-label studies, 0.5% of patients reported hallucinations during therapy with Ropinirole hydrochloride (2 of 390) but did not discontinue treatment and symptoms resolved.

Precautions

General

Dyskinesia

Ropinirole hydrochloride may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate preexisting dyskinesia in patients treated with L-dopa for Parkinson's disease. Decreasing the dose of L-dopa may ameliorate this side effect.

Renal Impairment

No dosage adjustment is needed in patients with mild to moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The use of Ropinirole hydrochloride in patients with severe renal impairment has not been studied.

Hepatic Impairment

The pharmacokinetics of Ropinirole have not been studied in patients with hepatic impairment. Since patients with hepatic impairment may have higher plasma levels and lower clearance, Ropinirole hydrochloride should be titrated with caution in these patients.

Events Reported With Dopaminergic Therapy

Withdrawal-Emergent Hyperpyrexia and Confusion

Although not reported with Ropinirole hydrochloride, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in anti-Parkinsonian therapy.

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown.

A small number of reports have been received of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy, in the development program and post-marketing experience for Ropinirole hydrochloride. While the evidence is not sufficient to establish a causal relationship between Ropinirole hydrochloride and these fibrotic complications, a contribution of Ropinirole hydrochloride cannot be completely ruled out in rare cases.

Melanoma

Epidemiologic studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Ropinirole hydrochloride for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Augmentation and Rebound in RLS

Reports in the literature indicate treatment of RLS with dopaminergic medications can result in a worsening of symptoms in the early morning hours, referred to as rebound. Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. The controlled trials of Ropinirole hydrochloride in patients with RLS excluded patients with augmentation and rebound and were generally not of sufficient duration to capture these phenomena. The frequency of augmentation and/or rebound after longer use of Ropinirole hydrochloride and the appropriate management of these events, have not been evaluated in controlled clinical trials.

Retinal Pathology

Albino Rats

Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all doses tested (equivalent to 0.6 to 20 times the maximum recommended human dose on a mg/m2 basis), but was statistically significant at the highest dose (50 mg/kg/day). Additional studies to further evaluate the specific pathology (e.g., loss of photoreceptor cells) have not been performed. Similar changes were not observed in a 2-year carcinogenicity study in albino mice or in rats or monkeys treated for one year. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding) may be involved.

Human

In order to evaluate the effect of Ropinirole hydrochloride in humans, ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible dose, L-dopa- controlled clinical study of Ropinirole in patients with Parkinson's disease. A total of 156 patients (78 on Ropinirole, mean dose 11.9 mg/day and 78 on levodopa, mean dose 555.2 mg/day) were evaluated for evidence of retinal dysfunction through electroretinograms. There was no clinically meaningful difference between the treatment groups in retinal function over the duration of the study.

Binding to Melanin

Ropinirole hydrochloride binds to melanin-containing tissues (i.e., eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days. It is not known if Ropinirole hydrochloride accumulates in these tissues over time.

Information for Patients

Physicians should instruct their patients to read the Patient Information leaflet before starting therapy with Ropinirole hydrochloride and to reread it upon prescription renewal for new information regarding the use of Ropinirole hydrochloride.

Patients should be instructed to take Ropinirole hydrochloride only as prescribed. If a dose is missed, patients should be advised not to double their next dose.

Ropinirole tablets can be taken with or without food. Patients may be advised that taking Ropinirole tablets with food may reduce the occurrence of nausea. However, this has not been established in controlled clinical trials.

Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment). Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods, and especially at the initiation of treatment with Ropinirole hydrochloride.

Patients should be alerted to the potential sedating effects associated with Ropinirole hydrochloride, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with Ropinirole hydrochloride to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician.

Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with Ropinirole hydrochloride and when taking concomitant medications that increase plasma levels of Ropinirole (e.g., ciprofloxacin).

Because of the possible additive sedative effects, caution should also be used when patients are taking alcohol or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with Ropinirole hydrochloride.

Patients should be informed they may experience hallucinations (unreal visions, sounds, or sensations) while taking Ropinirole hydrochloride. These were uncommon in patients taking Ropinirole hydrochloride for Restless Legs Syndrome. The risk is greater in patients with Parkinson's disease; the elderly are at greater risk tha

Clozapine Changzheng-Xinkai

Clozapine Changzheng-Xinkai may be available in the countries listed below.

Ingredient matches for Clozapine Changzheng-Xinkai

Clozapine

Clozapine is reported as an ingredient of Clozapine Changzheng-Xinkai in the following countries:

• China

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Silverin

Silverin may be available in the countries listed below.

Ingredient matches for Silverin

Sulfadiazine

Sulfadiazine silver (a derivative of Sulfadiazine) is reported as an ingredient of Silverin in the following countries:

• Oman

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Hydromorphone Hydrochloride Injection

Ingredient matches for Hydromorphone Hydrochloride Injection

Hydromorphone

Hydromorphone hydrochloride (a derivative of Hydromorphone) is reported as an ingredient of Hydromorphone Hydrochloride Injection in the following countries:

• United States

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Papaverina Hé Teofarma

Papaverina Hé Teofarma may be available in the countries listed below.

Ingredient matches for Papaverina Hé Teofarma

Papaverine

Papaverine hydrochloride (a derivative of Papaverine) is reported as an ingredient of Papaverina Hé Teofarma in the following countries:

• Italy

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Duplex T Topical

Generic Name: coal tar (Topical route)

kole tar

Commonly used brand name(s)

In the U.S.

• Betatar Gel


• Cutar Emulsion


• Denorex


• DHS Tar


• Doak Tar


• Duplex T


• Fototar


• Ionil-T Plus


• Medotar


• MG 217


• Neutrogena T/Derm


• Neutrogena T/Gel

In Canada

• Estar


• Liquor Carbonis Detergens


• Psorigel


• Spectro Tar Skin Wash


• Tar Distillate

Available Dosage Forms:

• Liquid


• Shampoo


• Lotion


• Solution


• Cream


• Gel/Jelly


• Soap


• Kit


• Ointment


• Bar


• Foam


• Emulsion

Therapeutic Class: Keratolytic

Uses For Duplex T

Coal tar is used to treat eczema, psoriasis, seborrheic dermatitis, and other skin disorders.

Some of these preparations are available only with your doctor's prescription.

Before Using Duplex T

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Coal tar products should not be used on infants, unless otherwise directed by your doctor. Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of this medicine in children with use in other age groups.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of this medicine in the elderly with use in other age groups.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of coal tar

This section provides information on the proper use of a number of products that contain coal tar. It may not be specific to Duplex T. Please read with care.

Use this medicine only as directed. Do not use more of it and do not use it more often than recommended on the label, unless otherwise directed by your doctor. To do so may increase the chance of side effects.

After applying coal tar, protect the treated area from direct sunlight and do not use a sunlamp for 72 hours, unless otherwise directed by your doctor, since a severe reaction may occur. Also, make sure you have removed all the coal tar medicine from your skin before you go back into direct sunlight or use a sunlamp.

Do not apply this medicine to infected, blistered, raw, or oozing areas of the skin.

Keep this medicine away from the eyes. If you should accidentally get some in your eyes, flush them thoroughly with water at once.

To use the cream or ointment form of this medicine:

• Apply enough medicine to cover the affected area, and rub in gently.

To use the gel form of this medicine:

• Apply enough gel to cover the affected area, and rub in gently. Allow the gel to remain on the affected area for 5 minutes, then remove excess gel by patting with a clean tissue.

To use the shampoo form of this medicine:

• Wet the scalp and hair with lukewarm water. Apply a generous amount of shampoo and rub into the scalp, then rinse. Apply the shampoo again, working up a rich lather, and allow to remain on the scalp for 5 minutes. Then rinse thoroughly.

To use the nonshampoo liquid form of this medicine:

• Some of these preparations are to be applied directly to dry or wet skin, some are to be added to lukewarm bath water, and some may be applied directly to dry or wet skin or added to lukewarm bath water. Make sure you know exactly how you should use this medicine. If you have any questions about this, check with your health care professional.


• If this medicine is to be applied directly to the skin, apply enough to cover the affected area, and rub in gently.


• Some of these preparations contain alcohol and are flammable. Do not use near heat, near open flame, or while smoking.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For eczema, psoriasis, seborrheic dermatitis, and other skin disorders:
  
  • For cleansing bar dosage form:
    
    • Adults—Use one or two times a day, or as directed by your doctor.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For cream dosage form:
    
    • Adults—Apply to the affected area(s) of the skin up to four times a day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For gel dosage form:
    
    • Adults—Apply to the affected area(s) of the skin one or two times a day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For lotion dosage form:
    
    • Adults—Apply directly to the affected area(s) of the skin or use as a bath, hand or foot soak, or as a hair rinse, depending on the product.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For ointment dosage form:
    
    • Adults—Apply to the affected area(s) of the skin two or three times a day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For shampoo dosage form:
    
    • Adults—Use once a day to once a week or as directed by your doctor.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For topical solution dosage form:
    
    • Adults—Apply to wet the skin or scalp, or use as a bath, depending on the product.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For topical suspension dosage form:
    
    • Adults—Use as a bath.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Duplex T

If this medicine is used on the scalp, it may temporarily discolor blond, bleached, or tinted hair.

Coal tar may stain the skin or clothing. Avoid getting it on your clothing. The stain on the skin will wear off after you stop using the medicine.

Duplex T Side Effects

In animal studies, coal tar has been shown to increase the chance of skin cancer.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

Rare

• Skin irritation not present before use of this medicine


• skin rash

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Stinging (mild)—especially for gel and solution dosage forms

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Duplex T Topical side effects (in more detail)

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More Duplex T Topical resources

• Duplex T Topical Side Effects (in more detail)
• Duplex T Topical Use in Pregnancy & Breastfeeding
• Duplex T Topical Support Group
• 4 Reviews for Duplex T Topical - Add your own review/rating

Compare Duplex T Topical with other medications

• Dermatitis
• Psoriasis
• Seborrheic Dermatitis

Alendil

Alendil may be available in the countries listed below.

Ingredient matches for Alendil

Alendronic Acid

Alendronic Acid sodium trihydrate (a derivative of Alendronic Acid) is reported as an ingredient of Alendil in the following countries:

• Brazil

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Custey

Custey may be available in the countries listed below.

Ingredient matches for Custey

Loperamide

Loperamide hydrochloride (a derivative of Loperamide) is reported as an ingredient of Custey in the following countries:

• Argentina

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Flomaxtra

Flomaxtra may be available in the countries listed below.

UK matches:

• Flomaxtra XL
• Flomaxtra XL, 400 micrograms, film-coated prolonged release tablet (SPC)

Ingredient matches for Flomaxtra

Tamsulosin

Tamsulosin hydrochloride (a derivative of Tamsulosin) is reported as an ingredient of Flomaxtra in the following countries:

• Australia


• New Zealand


• United Kingdom

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Glossary

SPC	Summary of Product Characteristics (UK)

Click for further information on drug naming conventions and International Nonproprietary Names.