Zesup

Zesup may be available in the countries listed below.

Ingredient matches for Zesup

Zinc Sulfate

Zinc Sulfate is reported as an ingredient of Zesup in the following countries:

• Bangladesh

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Fabozepam

Fabozepam may be available in the countries listed below.

Ingredient matches for Fabozepam

Bromazepam

Bromazepam is reported as an ingredient of Fabozepam in the following countries:

• Argentina

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Zefone

Zefone may be available in the countries listed below.

Ingredient matches for Zefone

Ceftriaxone

Ceftriaxone is reported as an ingredient of Zefone in the following countries:

• Ethiopia

Ceftriaxone disodium salt (a derivative of Ceftriaxone) is reported as an ingredient of Zefone in the following countries:

• Myanmar

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Opthaflox

Opthaflox may be available in the countries listed below.

Ingredient matches for Opthaflox

Ciprofloxacin

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

• Mexico

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Ibandronic Acid

Scheme

Rec.INN

ATC (Anatomical Therapeutic Chemical Classification)

M05BA06

CAS registry number (Chemical Abstracts Service)

0114084-78-5

Chemical Formula

C9-H23-N-O7-P2

Molecular Weight

319

Therapeutic Category

Calcium regulator

Chemical Name

[1-Hydroxy-3-(methylpentylamino)propylidene]diphosphonic acid

Foreign Names

• Acidum ibandronicum (Latin)
• Ibandronsäure (German)
• Acide ibandronique (French)
• Ácido ibandrónico (Spanish)

Generic Names

• Ibandronic Acid (OS: BAN)
• Bandronic Acid (IS)
• Ibandronate Sodium (OS: USAN)
• Sodium Ibandronate (OS: BANM)
• BM 210955 (IS: Boehringer Mannheim)

Brand Names

• Bondenza
  Faes, Spain



• Bondronat
  Roche, Armenia; Roche, Azerbaijan; Roche, Bosnia & Herzegowina; Roche, Bulgaria; Roche, Chile; Roche, China; Roche, Colombia; Roche, Georgia; Roche, Greece; Roche, Hong Kong; Roche, Indonesia; Roche, Ireland; Roche, Luxembourg; Roche, Oman; Roche, Portugal; Roche, Romania; Roche, Slovenia; Roche, Slovakia; Roche, Tunisia; Roche, Turkey; Roche, Taiwan; Roche, Venezuela; Roche, South Africa; Roche RX, Singapore



• Bonil
  Farmindustria, Peru



• Bonviva
  Roche, Colombia; Roche, Spain; Roche, Greece; Roche, Peru; Roche, Portugal; Roche, Slovakia; Roche, Thailand; Roche, Turkey



• Idena
  Tecnofarma, Peru



• Bandrobon
  Dupomar, Argentina



• Bondronat
  Hospira, Australia; Roche, Austria; Roche, Bangladesh; Roche, Belgium; Roche, Bahrain; Roche, Switzerland; Roche, Czech Republic; Roche, Germany; Roche, Denmark; Roche, Ecuador; Roche, Spain; Roche, Finland; Roche, France; Roche, United Kingdom; Roche, Croatia (Hrvatska); Roche, Hungary; Roche, Iceland; Roche, Italy; Roche, Netherlands; Roche, Norway; Roche, Philippines; Roche, Poland; Roche, Serbia; Roche, Sweden; Roche, Slovenia; Roche, Slovakia; Roche Diagnostic, Algeria; Syntex, Mexico



• Boniva
  GlaxoSmithKline, Georgia; GlaxoSmithKline, United States; Roche, United States



• Bonviva
  GlaxoSmithKline, Germany; Roche, Argentina; Roche, Austria; Roche, Bosnia & Herzegowina; Roche, Belgium; Roche, Bulgaria; Roche, Bulgaria; Roche, Bahrain; Roche, Switzerland; Roche, Chile; Roche, Czech Republic; Roche, Germany; Roche, Denmark; Roche, Ecuador; Roche, Finland; Roche, France; Roche, United Kingdom; Roche, Georgia; Roche, Croatia (Hrvatska); Roche, Hungary; Roche, Indonesia; Roche, Ireland; Roche, Italy; Roche, Luxembourg; Roche, Mexico; Roche, Netherlands; Roche, Norway; Roche, Oman; Roche, Philippines; Roche, Poland; Roche, Romania; Roche, Serbia; Roche, Sweden; Roche, Slovenia; Roche, Venezuela



• Elasterin
  Phoenix, Argentina



• Idena
  Raffo, Argentina

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Glossary

BAN	British Approved Name
BANM	British Approved Name (Modified)
IS	Inofficial Synonym
OS	Official Synonym
Rec.INN	Recommended International Nonproprietary Name (World Health Organization)
USAN	United States Adopted Name

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

Spironolacton PCH

Spironolacton PCH may be available in the countries listed below.

Ingredient matches for Spironolacton PCH

Spironolactone

Spironolactone is reported as an ingredient of Spironolacton PCH in the following countries:

• Netherlands

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May Cefuroxime

May Cefuroxime may be available in the countries listed below.

Ingredient matches for May Cefuroxime

Cefuroxime

Cefuroxime sodium salt (a derivative of Cefuroxime) is reported as an ingredient of May Cefuroxime in the following countries:

• Philippines

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Adecco

Adecco may be available in the countries listed below.

Ingredient matches for Adecco

Metformin

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

• Indonesia

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Vicks Sinex

UK matches:

• Vicks Sinex Decongestant Nasal Spray (SPC)
• Vicks Sinex Micromist (SPC)
• Vicks Sinex Soother (SPC)

Ingredient matches for Vicks Sinex

Oxymetazoline

Oxymetazoline hydrochloride (a derivative of Oxymetazoline) is reported as an ingredient of Vicks Sinex in the following countries:

• Australia


• Belgium


• Finland


• Italy


• Luxembourg


• Malta


• Netherlands


• New Zealand


• Switzerland


• United Kingdom


• United States

Phenylephrine

Phenylephrine hydrochloride (a derivative of Phenylephrine) is reported as an ingredient of Vicks Sinex in the following countries:

• United States

International Drug Name Search

Glossary

SPC	Summary of Product Characteristics (UK)

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

Requip-XL

ropinirole hydrochloride

Dosage Form: tablet, film coated, extended release
FULL PRESCRIBING INFORMATION

Indications and Usage for Requip-XL

Parkinson’s Disease

REQUIP XL (ropinirole extended-release tablets) is indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease.

Requip-XL Dosage and Administration

General Dosing Considerations

• REQUIP XL Extended-Release Tablets are taken once daily, with or without food. Taking REQUIP XL with food may reduce the occurrence of nausea; this has not been established in controlled clinical trials [see Clinical Pharmacology (12.3)].


• Tablets must be swallowed whole and must not be chewed, crushed, or divided.


• If a significant interruption in therapy with REQUIP XL has occurred, retitration of therapy may be warranted.

Dosing for Parkinson’s Disease

The starting dose is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at 1-week or longer intervals as appropriate, depending on therapeutic response and tolerability, up to a maximally recommended dose of 24 mg/day.

In clinical trials, dosage was initiated at 2 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 24 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 1 week or longer after each dose increment. Caution should be exercised during dose titration because too rapid a rate of titration may lead to dose selection that may not provide additional benefit, but that may increase the risk of adverse reactions [see Clinical Studies (14.2)]. Due to the flexible dosing design used in clinical studies, specific dose response information could not be determined.

When REQUIP XL is administered as adjunct therapy to L-dopa, the concurrent dose of L-dopa may be decreased gradually as tolerated. In the placebo-controlled advanced Parkinson’s disease study, the L-dopa dose was reduced once patients reached a dose of REQUIP XL of 8 mg/day. Overall, L-dopa dose reduction was sustained in 93% of patients treated with REQUIP XL and in 72% of patients on placebo. On average the L-dopa dose was reduced by 34% in patients treated with REQUIP XL [see Clinical Studies (14)].

REQUIP XL should be discontinued gradually over a 7-day period.

Switching From Immediate-Release Ropinirole Tablets to REQUIP XL

Patients may be switched directly from immediate-release ropinirole to REQUIP XL Tablets. The initial dose of REQUIP XL should most closely match the total daily dose of the immediate-release formulation of REQUIP, as shown in Table 1.

Table 1. Conversion from Immediate-Release REQUIP to REQUIP XL

Immediate-Release Ropinirole Tablets Total Daily Dose (mg)	REQUIP XL Tablets Total Daily Dose (mg)
0.75 to 2.25	2
3 to 4.5	4
6	6
7.5 to 9	8
12	12
15 to 18	16
21	20
24	24

Following conversion to REQUIP XL, the dose may be adjusted depending on therapeutic response and tolerability[see Dosage and Administration (2.2)].

Dosage Forms and Strengths

• 2 mg, pink, biconvex, capsule-shaped, film-coated, tablets debossed with “GS” and “3V2”


• 4 mg, light brown, biconvex, capsule-shaped, film-coated, tablets debossed with “GS” and “WXG”


• 6 mg, white, biconvex, capsule-shaped, film-coated, tablets debossed with “GS” and “11F”


• 8 mg, red, biconvex, capsule-shaped, film-coated, tablets debossed with “GS” and “5CC”


• 12 mg, green, biconvex, capsule-shaped, film-coated, tablets debossed with “GS” and “YX7”

Contraindications

None.

Warnings and Precautions

Falling Asleep During Activities of Daily Living

Patients treated with ropinirole 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 more than 1 year after initiation of treatment.

Among the 613 patients who received REQUIP XL in clinical trials, there were 5 cases of sudden onset of sleep and 2 cases of motor vehicle accident in which it is not known if falling asleep was a contributing factor.

During the 6-month trial in advanced Parkinson’s disease, somnolence was reported in 7% (14 of 202) of patients receiving REQUIP XL compared with 4% (7 of 191) of patients receiving placebo. During the 36-week trial in early Parkinson’s disease, somnolence was reported in 11% (16 of 140) of patients receiving REQUIP XL compared with 15% (22 of 149) of patients receiving the immediate-release formulation of REQUIP [see Adverse Reactions (6)]. However, because dose-response was not systematically studied with REQUIP XL, the occurrence of somnolence at the highest recommended doses may be higher than these reported frequencies [see Adverse Reactions (6)].

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 REQUIP XL, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with REQUIP XL such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin) [see Drug Interactions (7.1)]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating, etc.), REQUIP XL should ordinarily be discontinued [see Dosage and Administration for guidance in discontinuing REQUIP XL (2.2)]. If a decision is made to continue REQUIP XL, 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 during treatment with ropinirole in Parkinson’s disease patients.

In a placebo-controlled study involving patients with advanced Parkinson’s disease, syncope occurred in 2 of the 202 patients (1%) who received REQUIP XL, and in none of the 191 patients who received placebo.

Because the study of REQUIP XL excluded patients with significant cardiovascular disease, it is not known to what extent the estimated incidence figure applies to patients with Parkinson’s disease in clinical practice. Therefore, patients with significant cardiovascular disease should be treated with caution.

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. In addition, patients with Parkinson’s disease appear to have an impaired capacity to respond to a postural challenge. For these reasons, 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 Patient Counseling Information (17.2)].

In a placebo-controlled trial involving patients with advanced Parkinson’s disease, hypotension was reported as an adverse event in 5 of 202 patients (2%) receiving REQUIP XL and in none of the 191 patients receiving placebo. Orthostatic hypotension was reported as an adverse event in 5% of patients receiving REQUIP XL, and in 1% of placebo recipients.

An analysis of the randomized, double-blinded, placebo-controlled study in advanced Parkinson’s disease was conducted using a variety of adverse event terms possibly suggestive of hypotension, including hypotension, orthostatic hypotension, dizziness, vertigo, and blood pressure decreased. This analysis showed a higher incidence of these events with REQUIP XL (7%, 15 of 202) vs. placebo (3%, 6 of 191). This increased incidence was observed in a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this study.

Orthostatic vital signs (semi-supine to standing) were monitored throughout the study in the advanced Parkinson’s disease study and changes related to REQUIP XL (compared with placebo) from baseline were assessed.

The frequency of any orthostatic hypotension at any time during the study was 38% for REQUIP XL vs. 31% for placebo for mild to moderate systolic blood pressure decrements (≥20 mm Hg), 63% for REQUIP XL vs. 58% for placebo for mild to moderate diastolic blood pressure decrements (≥10 mm Hg), 10% for REQUIP XL vs. 7% for placebo for severe diastolic blood pressure decrements (≥20 mm Hg), and 23% for REQUIP XL vs. 19% for placebo for mild to moderate combined systolic and diastolic blood pressure decrements.

Significant decrements in blood pressure unrelated to standing were also reported in some patients taking REQUIP XL. In the semi-supine position, the frequency was 10% for REQUIP XL vs. 8% for placebo for severe systolic blood pressure decrease (≥40 mm Hg), and was 25% for REQUIP XL vs. 21% for placebo for severe diastolic blood pressure decrease (≥20 mm Hg).

The increased incidence for hypotension and/or orthostatic hypotension was observed in both the titration and maintenance phases and in some cases persisted into the maintenance period after developing in the titration phase.

Elevation of Blood Pressure and Changes in Heart Rate

In the placebo-controlled study in advanced Parkinson’s disease, there were no clear effects of REQUIP XL on average changes in blood pressure or heart rate compared with placebo. However, there was an increased incidence of patients treated with REQUIP XL who met various outlier criteria, as described below.

In the semi-supine position, the frequency was 8% for REQUIP XL vs. 5% for placebo for severe systolic blood pressure increase (≥40 mm Hg). In the standing position, the frequency was 9% for REQUIP XL vs. 6% for placebo for severe systolic blood pressure increase (≥40 mm Hg).

In the semi-supine position, the frequency was 23% for REQUIP XL vs. 18% for placebo for moderate pulse increase (≥15 beats/minute), and 19% for REQUIP XL vs. 17% for placebo for moderate pulse decrease (≥15 beats/minute). In the standing position, the frequency was 2% for REQUIP XL vs. <1% for placebo for severe pulse increase (≥30 beats/minute), and 24% for REQUIP XL vs. 19% for placebo for moderate pulse decrease (≥15 beats/minute).

The increased incidence for various elevations of systolic and/or diastolic blood pressure and/or changes in pulse was observed in both the titration and maintenance phases as well as persisting into the maintenance period after developing in the titration phase.

Elevation of blood pressure and/or changes in heart rate in patients taking REQUIP XL should be considered when treating patients with cardiovascular disease.

Hallucination

In the double-blind, placebo-controlled, advanced Parkinson’s disease trial 8% (17 of 202) of patients receiving REQUIP XL reported hallucination compared with 2% (4 of 191) patients receiving placebo. Hallucination led to discontinuation of treatment in 2% (4 of 202) of patients on REQUIP XL and 1% (2 of 191) of patients on placebo.

The incidence of hallucination is increased in patients over age 65. Coadministration of entacapone and L-dopa with ropinirole may also increase the risk of hallucination. In a placebo-controlled clinical trial, hallucination occurred in 0 of 43 patients taking entacapone plus L-dopa, in 9 of 155 patients taking REQUIP XL plus L-dopa (6%), and in 7 of 47 patients taking entacapone with REQUIP XL plus L-dopa (15%).

Dyskinesia

REQUIP XL 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 a dopaminergic drug may ameliorate this side effect.

Major Psychotic Disorders

Patients with a major psychotic disorder should ordinarily not be treated with REQUIP XL because of the risk of exacerbating the psychosis. In addition, many treatments for psychosis may decrease the effectiveness of REQUIP XL [see Drug Interactions (7.4)].

Events Reported With Dopaminergic Therapy

Withdrawal-Emergent Hyperpyrexia and Confusion: Although not reported during the clinical development of ropinirole, 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 dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with REQUIP XL as a prophylactic measure [see Dosage and Administration (2.2)].

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 reactions are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists, such as REQUIP or REQUIP XL, 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 postmarketing experience for ropinirole. In the clinical development program (N = 613), 2 patients treated with REQUIP XL had pleural effusion. While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be completely ruled out in rare cases.

Melanoma: Some epidemiologic studies have shown that patients with Parkinson’s disease have a higher risk (perhaps 2- to 4-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, was unclear. Ropinirole is one of the dopamine agonists used to treat Parkinson’s disease. Although ropinirole has not been associated with an increased risk of melanoma specifically, its potential role as a risk factor has not been systematically studied. In the clinical development program (N = 613), one patient treated with REQUIP XL and also levodopa/carbidopa developed melanoma. Patients using REQUIP XL should be made aware of these results and undergo periodic dermatologic screening.

Retinal Pathology

Human: Because of observations made in albino rats (see below), ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible-dose, l-dopa controlled clinical study of immediate-release ropinirole in patients with Parkinson’s disease. A total of 156 patients (78 on immediate-release ropinirole, mean dose 11.9 mg/day and 78 on l-dopa, 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.

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 (MRHD) of 24 mg/day on a mg/m2 basis), but was statistically significant at the highest dose (50 mg/kg/day). Retinal degeneration was not observed in pigmented rats after 3 months in a 2-year carcinogenicity study in albino mice, or in 1-year studies in monkeys or albino rats. The potential significance of this effect for 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.

Binding to Melanin

Ropinirole 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.

Adverse Reactions

The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:

• Falling asleep during activities of daily living (5.1)


• Syncope (5.2)


• Symptomatic hypotension, hypotension, postural/orthostatic hypotension (5.3)


• Elevation of blood pressure and changes in heart rate (5.4)


• Hallucination (5.5)


• Dyskinesia (5.6)


• Major psychotic disorders (5.7)


• Events with dopaminergic therapy (5.8)


• Retinal pathology (5.9)

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.

During the premarketing development of REQUIP XL, patients with advanced Parkinson’s disease received REQUIP XL or placebo as adjunctive therapy in 1 clinical trial. In a second trial, patients with early Parkinson’s disease were treated with REQUIP XL or the immediate-release formulation of REQUIP without L-dopa.

Advanced Parkinson’s Disease (With L-dopa): The most commonly observed adverse reactions (≥5% and numerically greater than placebo) in the 24-week, double-blind, placebo-controlled trial for the treatment of advanced Parkinson’s disease during treatment with REQUIP XL were, in order of decreasing incidence: dyskinesia, nausea, dizziness, hallucination, somnolence, abdominal pain/discomfort, and orthostatic hypotension.

Approximately 6% of 202 patients treated with REQUIP XL discontinued treatment due to adverse event(s) compared with 5% of 191 patients who received placebo. The adverse event most commonly causing discontinuation of treatment with REQUIP XL was hallucination (2%).

Table 2 lists adverse reactions that occurred with a frequency of at least 2% (and were numerically greater than placebo) in patients with advanced Parkinson’s disease treated with REQUIP XL who participated in the 26-week, double-blind, placebo-controlled study. In this study, either REQUIP XL or placebo was used as an adjunct to L -dopa. Adverse reactions were generally mild or moderate in intensity.

Table 2. Treatment-Emergent Adverse Reaction Incidence in a Double-Blind, Placebo-Controlled Trial in Advanced Stage Parkinson’s Disease (With L-dopa) (Events ≥2% of Patients Treated with REQUIP XL and >% with Placebo)

Body System/Adverse Reaction	REQUIP XL (n = 202) %	Placebo (n = 191) %
Ear and labyrinth disorders
Vertigo	4	2
Gastrointestinal disorders
Nausea	11	4
Constipation	4	2
Abdominal pain/discomfort	6	3
Diarrhea	3	2
Dry mouth	2	<1
General disorders
Edema peripheral	4	1
Injury, poisoning, and procedural complications
Fall*	2	1
Musculoskeletal and connective tissue disorders
Back pain	3	2
Nervous system disorders
Dyskinesia*	13	3
Dizziness	8	3
Somnolence	7	4
Psychiatric disorders
Hallucination	8	2
Anxiety	2	1
Vascular disorders
Orthostatic hypotension	5	1
Hypotension	2	0
Hypertension*	3	2

*Dose-related.

Although this study was not designed for optimally characterizing dose-related adverse reactions, there was a suggestion (based upon comparison of incidence of adverse reactions across dose ranges for REQUIP XL and placebo) that the incidence for dyskinesia, hypertension, and fall was dose-related to REQUIP XL.

The incidence for many adverse reactions with REQUIP XL treatment was increased relative to placebo (i.e., REQUIP XL % - Placebo % = treatment difference ≥2%) in either the titration or maintenance phases of the study. During the titration phase, an increased incidence (shown in descending order of % treatment difference) was observed for dyskinesia, nausea, abdominal pain/discomfort, orthostatic hypotension, dizziness, vertigo, hypertension, peripheral edema, and dry mouth. During the maintenance phase, an increased incidence was observed for dyskinesia, nausea, dizziness, hallucination, somnolence, fall, hypertension, abnormal dreams, constipation, chest pain, bronchitis, and nasopharyngitis. Some adverse reactions developing in the titration phase persisted (≥7 days) into the maintenance phase. These “persistent” adverse reactions included dyskinesia, hallucination, orthostatic hypotension, and dry mouth.

The incidence of adverse reactions was not clearly different between women and men.

Early Parkinson’s Disease (Without L-dopa): The most commonly observed adverse reactions (≥5%) in the 36-week early Parkinson’s disease trial during treatment with REQUIP XL were, in order of decreasing incidence: nausea (19%), somnolence (11%), abdominal pain/discomfort (7%), dizziness (6%), headache (6%), and constipation (5%). The type of adverse reactions and the frequency (i.e. incidence) with which they occurred were generally similar over the whole treatment period in this study of early Parkinson’s disease patients who were initially treated with REQUIP XL or the immediate-release formulation of REQUIP and subsequently crossed over to treatment with the other formulation.

During the titration phase, an increased incidence with REQUIP XL compared with the immediate-release formulation of REQUIP (i.e., REQUIP XL % - REQUIP IR % = treatment difference ≥2%), shown in descending order of % treatment difference, was observed for: constipation, hallucination, vertigo, abdominal pain/discomfort, nausea, vomiting, fall, headache, diarrhea, pyrexia, and flatulence. During the maintenance phase, an increased incidence was observed for fall, myalgia, and sleep disorder. Several adverse reactions developing in the titration phase persisted (≥7 days) into the maintenance phase. These “persistent” adverse reactions included: constipation, hallucination, muscle spasms, flatulence, insomnia, sleep disorder, abdominal pain/discomfort, cough, and nasopharyngitis.

Adverse Reactions Observed During the Clinical Development of the Immediate-Release Formulation of REQUIP for Parkinson’s Disease (Advanced and Early)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.

In patients with advanced Parkinson’s disease who were treated with the immediate-release formulation of REQUIP, the most common adverse reactions (≥5% treatment difference from placebo; presented in order of decreasing treatment difference frequency) were dyskinesia (21%), somnolence (12%), nausea (12%), dizziness (10%), confusion (7%), hallucinations (6%), headache (5%), and increased sweating (5%). In patients with early Parkinson’s disease who were treated with the immediate-release formulation of REQUIP, the most common adverse reactions (≥5% treatment difference from placebo; presented in order of decreasing treatment difference frequency) were nausea (38%), somnolence (34%), dizziness (18%), syncope (11%), viral infection (8%), fatigue (7%), leg edema (6%), asthenia (5%), and dyspepsia (5%).

Drug Interactions

P450 Interaction

In vitro metabolism studies showed that CYP1A2 is the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole. Therefore, if therapy with a drug known to be a potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with ropinirole, adjustment of the dose of ropinirole may be required.

Coadministration of ciprofloxacin, an inhibitor of CYP1A2, with immediate-release ropinirole increased the AUC of ropinirole by 84% on average and Cmax by 60% [see Clinical Pharmacology (12.3)].

Cigarette smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking. In one study in patients with Restless Legs Syndrome, cigarette smokers had an approximate 30% lower Cmax and a 38% lower AUC than did nonsmokers, when those parameters were normalized for dose.

There is no evidence of interaction between ropinirole and other CYP1A2 substrates (e.g., theophylline).

Ropinirole and its circulating metabolites do not inhibit or induce P450 enzymes therefore ropinirole is unlikely to affect the pharmacokinetics of other drugs by a P450 mechanism [see Clinical Pharmacology (12.3)].

L-dopa

Coadministration of carbidopa + L-dopa (SINEMET®*) with immediate-release ropinirole had no effect on the steady-state pharmacokinetics of ropinirole. Oral administration of immediate-release ropinirole increased mean steady-state Cmax of L-dopa by 20%, but its AUC was unaffected [see Clinical Pharmacology (12.3)].

Estrogens

Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy [HRT]) reduced the oral clearance of ropinirole by approximately 35%. Dosage adjustment is not needed for initiating REQUIP XL in patients on estrogen therapy because patients are individually titrated with REQUIP XL to tolerance or adequate effect. If estrogen therapy is stopped or started during treatment with REQUIP XL, then adjustment of the dose of REQUIP XL may be required.

Dopamine Antagonists

Since ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may diminish the effectiveness of REQUIP XL. Patients with a history or presence of major psychotic disorders should be treated with dopamine agonists only if the potential benefits outweigh the risks.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies using ropinirole in pregnant women. REQUIP XL should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

In animal reproduction studies, ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects. Treatment of pregnant rats with ropinirole during organogenesis resulted in decreased fetal body weight, increased fetal death, and digital malformations at 24, 36, and 60 times the MRHD, respectively. The combined administration of ropinirole at 8 times the MRHD and a clinically relevant dose of L-dopa to pregnant rabbits during organogenesis produced a greater incidence and severity of fetal malformations (primarily digit defects) than were seen in the offspring of rabbits treated with L-dopa alone. In a perinatal-postnatal study in rats, impaired growth and development of nursing offspring and altered neurological development of female offspring were observed when dams were treated with 4 times the MRHD.

Nursing Mothers

Ropinirole inhibits prolactin secretion in humans and could potentially inhibit lactation.

Ropinirole has been detected in the milk of lactating rats. Although many drugs are excreted in human milk, transfer of ropinirole into human milk has not been demonstrated. Due to the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of ropinirole to the mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

Geriatric Use

Dosage adjustment is not necessary in the elderly (above 65 years), as the dose of REQUIP XL is to be individually titrated to clinical response [see Clinical Pharmacology (12.3)]. Pharmacokinetic studies conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients above 65 years of age compared to younger patients.

Of the total number of patients who participated in clinical trials of REQUIP XL for Parkinson’s disease, 387 patients were 65 and over and 107 patients were 75 and over. Among patients receiving REQUIP XL, hallucination was more common in elderly subjects (10%) compared with non-elderly subjects (2%). The incidence of overall adverse events increased with increasing age for both patients receiving REQUIP XL and placebo.

Renal Impairment

No dosage adjustment of ropinirole is needed in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The use of ropinirole 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 should be titrated with caution in these patients.

Drug Abuse and Dependence

Controlled Substance

Ropinirole is not a controlled substance.

Dependence

Animal studies and human clinical trials with ropinirole did not reveal any potential for drug-seeking behavior or physical dependence.

Overdosage

Human Overdose Experience

In the Parkinson’s disease program, there have been patients who accidentally or intentionally took more than their prescribed dose of ropinirole. The largest overdose reported with immediate-release ropinirole in clinical trials was 435 mg taken over a 7-day period (62.1 mg/day). Of patients who received a dose greater than 24 mg/day, reported symptoms included adverse events commonly reported during dopaminergic therapy (nausea, dizziness), as well as visual hallucination, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Additional symptoms reported for doses of 24 mg or less or for overdoses of unknown amount included vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state.

Overdose Management

The symptoms of overdose with ropinirole are generally related to its dopaminergic activity; these symptoms may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide. General supportive measures are recommended. Vital signs should be maintained, if necessary. Removal of any unabsorbed material (e.g., by gastric lavage) may be considered.

Requip-XL Description

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

The structural formula is:

Ropinirole hydrochloride is a white to yellow solid with a melting range of 243° to 250°C and a solubility of 133 mg/mL in water.

REQUIP XL Extended-Release Tablets are formulated as a three-layered tablet with a central, active-containing, slow-release layer, and 2 placebo outer layers acting as barrier layers which control the surface area available for drug release. Each biconvex, capsule-shaped tablet contains 2.28 mg, 4.56 mg, 6.84 mg, 9.12 mg, or 13.68 mg ropinirole hydrochloride equivalent to ropinirole 2 mg, 4 mg, 6 mg, 8 mg, or 12 mg, respectively. Inactive ingredients consist of carboxymethylcellulose sodium, colloidal silicon dioxide, glyceryl behenate, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, mannitol, povidone, and one or more of the following: FD&C Yellow No. 6 aluminum lake, FD&C Blue No. 2 aluminum lake, ferric oxides (black, red, yellow), polyethylene glycol 400, titanium dioxide.

Requip-XL - 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.

The precise mechanism of action of ropinirole 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.

Pharmacodynamics

Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure with resulting postural hypotension, especially during dose escalation. In some subjects in clinical trials, blood pressure changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus arrest with syncope.

The mechanism of postural hypotension induced by ropinirole 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 suppressed serum prolactin concentrations in healthy male volunteers.

Immediate-release ropinirole had no dose-related effect on ECG wave form and rhythm in young, healthy, male volunteers in the range of 0.01 to 2.5 mg. Immediate-release ropinirole 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 on QTc intervals at higher exposures achieved either due to drug interactions, hepatic impairment, or at higher doses has not been systematically evaluated.

Pharmacokinetics

Absorption: In clinical studies with immediate-release ropinirole, over 88% of a radiolabeled dose was recovered in urine, and the absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect.

Ropinirole displayed linear kinetics up to doses of 24 mg/day (8 mg immediate-release, 3 times a day). Increase in systemic exposure of ropinirole following oral administration of 2 to 12 mg of REQUIP XL was approximately dose-proportional. For REQUIP XL, steady-state concentrations of ropinirole are expected to be achieved within 4 days of dosing.

Relative bioavailability of REQUIP XL Extended-Release Tablets compared with immediate-release tablets was approximately 100%. In a repeat-dose study in patients with Parkinson’s disease using REQUIP XL 8 mg, the dose-normalized AUC(0-24) and Cmin for REQUIP XL and immediate-release ropinirole were similar. Dose-normalized Cmax was, on average, 12% lower for REQUIP XL than for the immediate-release formulation and the median time-to-peak concentration was 6 to 10 hours. In a single-dose study, administration of REQUIP XL to healthy volunteers with food (i.e., high-fat meal) increased AUC by approximately 30% and Cmax by approximately 44%, compared with dosing under fasted conditions. In a repeat-dose study in patients with Parkinson’s disease, food (i.e., high-fat meal) increased AUC by approximately 20% and Cmax by approximately 44%; Tmax was prolonged by 3 hours (median prolongation) compared with dosing under fasted conditions [see Dosage and Administr

Pyrethia

Pyrethia may be available in the countries listed below.

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Promethazine

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

• Japan

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Biapenem

Scheme

Rec.INN

ATC (Anatomical Therapeutic Chemical Classification)

J01DH05

CAS registry number (Chemical Abstracts Service)

0120410-24-4

Chemical Formula

C15-H18-N4-O4-S

Molecular Weight

350

Therapeutic Category

Antibacterial: Beta-lactam

Chemical Names

(1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]-triazolium-6-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate

5H-Pyrazolo[1,2-a][1,2,4]triazol-4-ium, 6-[[2-carboxy-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-, hydroxide, inner salt, [4R-[4α,5ß,6ß(R*)]]-

6-{[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio}-6,7-dihydro-5H-pyrazololo[1,2-a]-s-triazol-4-ium hydroxide, inner salt (WHO)

6-{[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio}-6,7-dihydro-5H-pyrazololo[1,2-a][1,2,4]triazol-4-ium hydroxide, inner salt

Foreign Names

• Biapenem (Latin)
• Biapenem (German)
• Biapénem (French)
• Biapenem (Spanish)

Generic Names

• Biapenem (OS: USAN, JAN)
• CL 186815 (IS)
• L-627 (IS)
• LJC 10627 (IS)
• UNII-YR5U3L9ZH1 (IS)

Brand Name

• Omegacin
  Meiji Seika Kaisha, Japan

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Glossary

IS	Inofficial Synonym
JAN	Japanese Accepted Name
OS	Official Synonym
Rec.INN	Recommended International Nonproprietary Name (World Health Organization)
USAN	United States Adopted Name
WHO	World Health Organization

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

Quinapril Katwijk

Quinapril Katwijk may be available in the countries listed below.

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Quinapril

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

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