Ridan may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Iron Dextran is reported as an ingredient of Ridan in the following countries:
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Enoksetin may be available in the countries listed below.
Enoxacin is reported as an ingredient of Enoksetin in the following countries:
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Edase-D may be available in the countries listed below.
Diclofenac potassium salt (a derivative of Diclofenac) is reported as an ingredient of Edase-D in the following countries:
Serrapeptase is reported as an ingredient of Edase-D in the following countries:
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Ergotamine Tartrate may be available in the countries listed below.
Ergotamine Tartrate (BANM, JAN) is known as Ergotamine in the US.
International Drug Name Search
Glossary
| BANM | British Approved Name (Modified) |
| JAN | Japanese Accepted Name |
Epitard may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Phenytoin sodium salt (a derivative of Phenytoin) is reported as an ingredient of Epitard in the following countries:
International Drug Name Search
Endofer may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Iron Dextran is reported as an ingredient of Endofer in the following countries:
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Fudone may be available in the countries listed below.
Famotidine is reported as an ingredient of Fudone in the following countries:
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Finasterid Alternova may be available in the countries listed below.
Finasteride is reported as an ingredient of Finasterid Alternova in the following countries:
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Cytarabine-Mayne may be available in the countries listed below.
Cytarabine is reported as an ingredient of Cytarabine-Mayne in the following countries:
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Tramadol Copyfarm may be available in the countries listed below.
Tramadol hydrochloride (a derivative of Tramadol) is reported as an ingredient of Tramadol Copyfarm in the following countries:
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Meladinina may be available in the countries listed below.
Methoxsalen is reported as an ingredient of Meladinina in the following countries:
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Carace®20 Plus
'Carace' 20 Plus: Each tablet contains 20 mg lisinopril and 12.5 mg hydrochlorothiazide.
Tablets
'Carace' 20 Plus: Yellow, hexagonal scored tablet with the product code 'MSD 140' on one side.
For the management of mild to moderate hypertension in patients who have been stabilised on the individual components given in the same proportions.
Route of administration: Oral
Adults
Essential hypertension: The usual dosage of 'Carace' Plus is 1 tablet, administered once daily. If necessary, the dosage may be increased to 2 tablets, administered once daily.
Dosage in renal insufficiency: Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency).
'Carace' Plus is not to be used as initial therapy in any patient with renal insufficiency.
In patients with creatinine clearance of >30 and <80 ml/min, 'Carace' Plus may be used, but only after titration of the individual components.
Prior diuretic therapy:
Symptomatic hypotension may occur following the initial dose of 'Carace' Plus: this is more likely in patients who are volume and/or salt depleted as a result of prior diuretic therapy. If possible, the diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with lisinopril alone, in a 2.5 mg dose.
Use in the elderly
Lisinopril was equally effective in elderly (65 years or older) and non-elderly hypertensive patients. In elderly hypertensive patients, monotherapy with lisinopril was as effective in reducing diastolic blood pressure as monotherapy with either hydrochlorothiazide or atenolol. In clinical studies, age did not affect the tolerability of lisinopril.
In clinical studies the efficacy and tolerability of lisinopril and hydrochlorothiazide, administered concomitantly, were similar in both elderly and younger hypertensive patients.
Paediatric Use
Safety and effectiveness in children have not been established.
'Carace' Plus is contraindicated in patients with anuria or aortic stenosis or hyperkalaemia.
'Carace' Plus is contraindicated in patients who are hypersensitive to any component of the product.
'Carace' Plus is contraindicated in patients with a history of angioneurotic oedema relating to previous treatment with an angiotensin-converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.
'Carace' Plus is contraindicated in patients who are hypersensitive to other sulphonamide-derived drugs.
The use of 'Carace' Plus during pregnancy is not recommended. When pregnancy is detected 'Carace' Plus should be discontinued as soon as possible, unless it is considered life-saving for the mother.
'Carace' Plus is contraindicated in lactating women who are breast-feeding infants. It is not known whether lisinopril is excreted in human milk. Thiazides do appear in human milk. See also 'Breast-feeding mothers' under 'Pregnancy and Lactation'.
Hypotension and electrolyte/fluid imbalance: As with all antihypertensive therapy, symptomatic hypotension may occur in some patients. This was rarely seen in uncomplicated hypertensive patients but is more likely in the presence of fluid or electrolyte imbalance, e.g. volume depletion, hyponatraemia, hypochloraemic alkalosis, hypomagnesaemia or hypokalaemia which may occur from prior diuretic therapy, dietary salt restriction, dialysis, or during intercurrent diarrhoea or vomiting. Periodic determination of serum electrolytes should be performed at appropriate intervals in such patients.
Particular consideration should be given when therapy is administered to patients with ischaemic heart or cerebrovascular disease, because an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses. Following restoration of effective blood volume and pressure, reinstitution of therapy at reduced dosage may be possible; or either of the components may be used appropriately alone.
Aortic stenosis/Hypertrophic cardiomyopathy: As with all vasodilators, ACE inhibitors should be given with caution to patients with obstruction in the outflow tract of the left ventricle.
Renal function impairment: Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency). 'Carace' Plus should not be administered to patients with renal insufficiency (creatinine clearance <80 ml/min) until titration of the individual components has shown the need for the doses present in the combination tablet.
Some hypertensive patients, with no apparent pre-existing renal disease, have developed usually minor and transient increases in blood urea and serum creatinine when lisinopril has been given concomitantly with a diuretic. If this occurs during therapy with 'Carace' Plus, the combination should be discontinued. Reinstitution of therapy at reduced dosage may be possible, or either of the components may be used appropriately alone.
In some patients, with bilateral renal artery stenosis or stenosis of the single artery to a solitary kidney, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen with angiotensin-converting enzyme (ACE) inhibitors.
Haemodialysis patients: The use of 'Carace' Plus is not indicated in patients requiring dialysis for renal failure. A high incidence of anaphylactoid reactions has been reported in patients dialysed with high-flux membranes (e.g. AN 69) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Anaphylactoid reactions during LDL apheresis: Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Hepatic disease: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Surgery/anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required.
Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Thiazide therapy may precipitate hyperuricaemia and/or gout in certain patients. However, lisinopril may increase urinary uric acid and thus may attenuate the hyperuricaemic effect of hydrochlorothiazide.
Hypersensitivity/angioneurotic oedema: Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin-converting enzyme inhibitors, including lisinopril. This may occur at anytime during treatment. In such cases, 'Carace' Plus should be discontinued promptly, and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient.
In those instances where swelling has been confined to the face and lips, the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioneurotic oedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy (which may include subcutaneous ephinephrine (adrenaline) solution 1:1,000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway) should be administered promptly.
Intestinal angioedema has also been reported very rarely in patients treated with ACE inhibitors and should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.
Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. (See also 'Contraindications').
In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.
Anaphylactoid Reactions during Hymenoptera Desensitisation: Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom (e.g. Bee or Wasp venom) have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.
Cough: Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent, and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Serum potassium: The potassium-losing effect of thiazide diuretics is usually attenuated by the potassium-conserving effect of lisinopril.
The use of potassium supplements, potassium-sparing agents or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. If concomitant use of 'Carace' Plus and any of these agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
Antidiabetic drugs: Epidemiological studies have suggested that concomitant administration of ACE-inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. Long term controlled clinical trials with lisinopril have not confirmed these findings and do not preclude the use of lisinopril in diabetic patients. It is advised, however that these patients be monitored. (See below for information regarding antidiabetic drugs and thiazide diuretics.)
Lithium: Diuretic agents and ACE inhibitors reduce the renal clearance of lithium and add a high risk of lithium toxicity; concomitant use is not recommended. Refer to prescribing information for lithium preparations before use of such preparations.
Narcotic drugs/antipsychotics: Postural hypotension may occur with ACE inhibitors.
Alcohol: Alcohol may enhance the hypotensive effect of any antihypertensive.
Other agents: Indometacin may diminish the antihypertensive effect of concomitantly administered 'Carace' Plus. In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs the co-administration of ACE inhibitors may result in further deterioration of renal function. These effects are usually reversible. The antihypertensive effect of 'Carace' Plus may be potentiated when given concomitantly with other agents likely to cause postural hypotension.
Non-depolarising muscle relaxants: Thiazides may increase the responsiveness to tubocurarine.
Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids, or procainamide: Concomitant administration with ACE inhibitors may lead to an increased risk of leucopenia.
Antacids: Induce decreased bioavailability of ACE inhibitors.
Sympathomimetics: May reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired effect is being obtained.
Ciclosporin: Increase the risk of hyperkalaemia with ACE inhibitors.
When administered concurrently, the following drugs may interact with thiazide diuretics:
Barbiturates or narcotics: Potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required. (See above for information regarding antidiabetic drugs and lisinopril).
Colestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either colestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.
Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalaemia.
Pressor amines (e.g. epinephrine (adrenaline)): Possible decreased response to pressor amines but not sufficient to preclude their use.
Non-steroidal anti-inflammatory drugs: In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of diuretics.
Pregnancy
The use of 'Carace' Plus during pregnancy is not recommended. When pregnancy is detected 'Carace' Plus should be discontinued as soon as possible, unless it is considered life-saving for the mother.
ACE inhibitors can cause foetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters. Use of ACE inhibitors during this period has been associated with foetal and neonatal injury including hypotension, renal failure, hyperkalaemia, and/or skull hypoplasia in the newborn. Maternal oligohydramnios, presumably representing decreased foetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development.
These adverse effects to the embryo and foetus do not appear to have resulted from intrauterine ACE inhibitor exposure limited to the first trimester.
The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and foetus to unnecessary hazard including foetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult.
If 'Carace' Plus is used during pregnancy, the patient should be apprised of the potential hazard to the foetus. In those rare cases where use during pregnancy is deemed essential, serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is detected, 'Carace' Plus should be discontinued unless it is considered life-saving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the foetus has sustained irreversible injury.
Infants whose mothers have taken 'Carace' Plus should be closely observed for hypotension, oliguria and hyperkalaemia. Lisinopril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion. There is no experience with the removal of hydrochlorothiazide, which also crosses the placenta, from the neonatal circulation.
Lactation
Breast-feeding mothers: It is not known whether lisinopril is secreted in human milk; however, thiazides do appear in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue 'Carace' Plus, taking into account the importance of the drug to the mother.
Usually 'Carace' Plus does not interfere with the ability to drive and to operate machinery. Patients should be instructed to first determine how they respond to 'Carace' Plus before performing hazardous tasks.
'Carace' Plus is usually well tolerated. In clinical studies, side effects have usually been mild and transient, and in most instances have not required interruption of therapy. The side effects that have been observed have been limited to those reported previously with lisinopril or hydrochlorothiazide.
One of the most common clinical side effects was dizziness, which generally responded to dosage reduction and seldom required discontinuation of therapy. Other, less frequent, side effects were headache, dry cough, fatigue, and hypotension including orthostatic hypotension.
Still less common were diarrhoea, nausea, vomiting, pancreatitis, dry mouth, rash, gout, palpitation, chest discomfort, muscle cramps and weakness, paraesthesia, asthenia, and impotence.
Hypersensitivity/angioneurotic oedema: Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely. Intestinal angioedema has also been reported very rarely in patients treated with ACE inhibitors. (see 'Precautions').
A symptom complex has been reported which may include some or all of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leucocytosis. Rash, photosensitivity, or other dermatological manifestations may occur.
Laboratory test findings: Laboratory side effects have rarely been of clinical importance. Occasional hyperglycaemia, hyperuricaemia and hyperkalaemia or hypokalaemia have been noted. Usually minor and transient increases in blood urea nitrogen and serum creatinine have been seen in patients without evidence of pre-existing renal impairment. If such increases persist, they are usually reversible upon discontinuation of 'Carace' Plus. Small decreases in haemoglobin and haematocrit have been reported frequently in hypertensive patients treated with 'Carace' Plus but were rarely of clinical importance unless another cause of anaemia co-existed. Rarely, elevation of liver enzymes and/or serum bilirubin have occurred, but a causal relationship to 'Carace' Plus has not been established.
Other side effects reported with the individual components alone, and which may be potential side effects with 'Carace' Plus, are:
Lisinopril: Myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high-risk patients (see 'Precautions'), tachycardia, abdominal pain, hepatitis - either hepatocellular or cholestatic jaundice, mood alterations, mental confusion, bronchospasm, urticaria, pruritis, diaphoresis, alopecia, uraemia, oliguria/anuria, renal dysfunction, acute renal failure, bone marrow depression manifest as anaemia and/or thrombocytopenia and/or leucopenia, hyponatraemia. Rare cases of neutropenia have been reported, although no causal relationship has been established. There have been reports of haemolytic anaemia in patients taking lisinopril, although no causal relationship has been established.
Hydrochlorothiazide: Anorexia, gastric irritation, constipation, jaundice (intrahepatic cholestatic jaundice), sialoadenitis, vertigo, xanthopsia, leucopenia, agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, purpura, photosensitivity, urticaria, necrotising angiitis (vasculitis, cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary oedema, anaphylactic reactions, toxic epidermal necrolysis, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance including hyponatraemia, muscle spasm, restlessness, transient blurred vision, renal failure, renal dysfunction, and interstitial nephritis.
No specific information is available on the treatment of overdosage with 'Carace' Plus. Treatment is symptomatic and supportive. Therapy with 'Carace' Plus should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, if ingestion is recent, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.
Lisinopril: The most likely features of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution, if available angiotensin II may be beneficial.
Lisinopril may be removed from the general circulation by haemodialysis. (See 'Special Warnings and Precautions, Haemodialysis Patients').
Hydrochlorothiazide: The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac arrhythmias.
'Carace' Plus contains antihypertensive and diuretic activity. Lisinopril and hydrochlorothiazide have been used alone and concurrently for the treatment of hypertension where their effects are approximately additive.
Lisinopril is an inhibitor of the angiotensin-converting enzyme (ACE). Inhibition of the formation of angiotensin II results in vasodilation and a fall in blood pressure.
Hydrochlorothiazide is a diuretic and antihypertensive agent. Use of this agent alone results in increased renin secretion. Although lisinopril alone is antihypertensive, even in patients with low renin hypertension, concomitant administration with hydrochlorothiazide results in a greater reduction in blood pressure. Lisinopril attenuates the potassium loss associated with hydrochlorothiazide.
In clinical studies, peak serum concentrations of lisinopril occurred within about 6 to 8 hours following oral administration. Declining serum concentrations exhibited a prolonged terminal phase which did not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and was not proportional to dose. Lisinopril did not appear to be bound to other plasma proteins.
Lisinopril does not undergo significant metabolism and is excreted unchanged predominantly in the urine. Based on urinary recovery in clinical studies, the extent of absorption of lisinopril was approximately 25%. Lisinopril absorption was not influenced by the presence of food in the gastrointestinal tract.
On multiple dosing, lisinopril exhibited an effective accumulation half-life of 12 hours.
In patients with renal insufficiency, disposition of lisinopril was similar to that in patients with normal renal function until glomerular filtration rate reached 30 ml/min or less; peak and trough lisinopril levels, and time to peak then increased and time to steady state was sometimes prolonged. Animal studies indicate lisinopril crosses the blood-brain barrier poorly. No clinically significant pharmacokinetic interactions occurred when lisinopril was used concomitantly with propranolol, digoxin or hydrochlorothiazide.
When plasma levels of hydrochlorothiazide have been followed for at least 24 hours the plasma half-life has been observed to vary between 5.6 and 14.8 hours. Hydrochlorothiazide is not metabolised but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
Concomitant multiple doses of lisinopril and hydrochlorothiazide have little or no effect on the bioavailability of these drugs. The combination tablet is bioequivalent to concomitant administration of the separate entities.
Lisinopril and hydrochlorothiazide are well established in medical use. Preclinical data is broadly consistent with clinical experience. For reproduction toxicity, see section 4.6.
Mannitol BP
Calcium Hydrogen Phosphate BP
Blue FD & C Aluminium Lake (E132) ('Carace' 10 Plus)
Yellow Ferric Oxide (E172) ('Carace' 20 Plus)
Maize Starch BP
Pregelatinised Starch BP
Magnesium Stearate EP
Not applicable.
30 months - Bottles
36 months - Blisters
Store in a dry place below 25°C.
HDPE bottles of 30, 56 or 100 tablets.
Blister packs of 2, 28, 30, 56, 84 or 100 tablets.
Not applicable.
Merck Sharp & Dohme Limited
Hertford Road
Hoddesdon
Hertfordshire
EN11 9BU
Carace 20 Plus PL 00025/0535
11 February 2009
November 2011
POM
© Merck Sharp & Dohme Limited 2011. All rights reserved.
SPC.CARPLUS.11.UK.3526
Xipamid AbZ may be available in the countries listed below.
Xipamide is reported as an ingredient of Xipamid AbZ in the following countries:
International Drug Name Search
Cayston 75 mg powder and solvent for nebuliser solution
Cayston contains aztreonam lysine (formed in situ from 75 mg aztreonam) as a sterile lyophilised powder in a vial and a 1 ml ampoule of sterile solvent (0.17% w/v sodium chloride). After reconstitution of the powder in the solvent, the nebuliser solution contains 75 mg aztreonam (as lysine).
For a full list of excipients, see section 6.1.
Powder and solvent for nebuliser solution.
White to off-white, lyophilised powder.
Cayston is indicated for the suppressive therapy of chronic pulmonary infections due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF) aged 18 years and older.
The primary support for this indication is based on two single 28-day course placebo-controlled studies. The data to support the sustainability of the observed short term benefit over subsequent courses of treatment are limited (see section 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Posology
Patients should use a bronchodilator before each dose of Cayston. Short acting bronchodilators can be taken between 15 minutes and 4 hours and long acting bronchodilators can be taken between 30 minutes and 12 hours prior to each dose of Cayston.
For patients receiving several respiratory therapies, the recommended order is:
1. bronchodilator
2. dornase alfa
3. chest physiotherapy
4. other inhaled medicinal products
5. Cayston.
Adults
The recommended dose for adults is 75 mg three times per 24 hours for 28 days.
Doses should be taken at least 4 hours apart.
Multiple course, controlled efficacy data are not yet available (see section 5.1). Additional courses, beyond the initial 28-day course, should be considered only at the discretion of the physician. If additional courses are prescribed, a minimum of 28 days without Cayston is recommended.
Paediatric population
Cayston is not recommended for use in children below the age of 18 years due to insufficient data on safety and efficacy (see section 5.1).
Elderly population
Clinical studies with Cayston did not include sufficient numbers of patients aged 65 years and over to determine whether they responded differently from younger patients. If Cayston is to be prescribed to the elderly then the posology is the same as for adults.
Renal impairment
Aztreonam is known to be excreted renally and therefore administration of Cayston in patients with renal impairment (serum creatinine > 2 times upper limit of normal) should be undertaken with caution. No dose adjustment is necessary in cases of renal impairment since the systemic concentration of aztreonam following inhaled administration of Cayston is very low (approximately 1% of the concentration resulting from a dose of 500 mg aztreonam for injection).
Hepatic impairment
There are no data on the use of Cayston in patients with severe hepatic impairment (ALT or AST greater than 5 times the upper limit of normal). No dose adjustment is necessary in cases of hepatic impairment.
Method of administration
Cayston is only for inhalation use.
Cayston should only be used with the Altera Nebuliser Handset and Altera Aerosol Head connected to an Altera Control Unit or an eFlow rapid Control Unit. For instructions on reconstitution of the medicinal product before administration, see section 6.6.
Hypersensitivity to the active substance or to any of the excipients.
Allergic reactions
If an allergic reaction to Cayston does occur, stop administration of the medicinal product and initiate treatment as appropriate. The occurrence of rash may be indicative of an allergic reaction to Cayston.
Cross-reactivity may occur in patients with a history of allergy to beta-lactam antibiotics, such as penicillins, cephalosporins, and/or carbapenems. Animal and human data demonstrate low risk of cross-reactivity between aztreonam and beta-lactam antibiotics. Aztreonam, a monobactam, is only weakly immunogenic. Caution is advised when administering Cayston to patients if they have a history of beta-lactam allergy.
The following rare and severe adverse reactions, although these have not been observed to date with Cayston, have been reported after parenteral use of other aztreonam containing products: toxic epidermal necrolysis, anaphylaxis, purpura, erythema multiforme, exfoliative dermatitis, urticaria, petechiae, pruritus, diaphoresis.
Bronchospasm
Bronchospasm is a complication associated with nebulised therapies. Patients were pre-treated with a bronchodilator before dosing with study therapy. An acute reduction of 1) following administration of study therapy was observed in 3% of patients treated with Cayston and 4% of patients receiving placebo despite pre-treatment with a bronchodilator before dosing with study therapy. Patients should use a bronchodilator before each dose of Cayston. If a case of bronchospasm is suspected to be part of an allergic reaction appropriate measures should be taken (see “allergic reactions” paragraph above).
Other precautions
In clinical studies, the efficacy and safety of Cayston were not tested in patients with FEV1 % predicted < 25% or > 75%. Patients with Burkholderia cepacia isolated from sputum within the previous 2 years were excluded from the clinical studies.
Aztreonam for injection must not be used in the Altera or other nebulisers. Aztreonam for injection has not been formulated for inhalation, and contains arginine, a substance known to cause pulmonary inflammation.
The development of antibiotic-resistant P. aeruginosa and superinfection with other pathogens represent potential risks associated with antibiotic therapy. Development of resistance during inhaled aztreonam therapy could limit treatment options during acute exacerbations. In clinical studies of Cayston, no increases of clinical significance were observed in the prevalence of antibiotic-resistant P. aeruginosa or other bacterial respiratory pathogens among patients treated three times daily with Cayston. Among patients with multidrug-resistant P. aeruginosa, improvements in respiratory symptoms and pulmonary function were observed following treatment with Cayston. An increased prevalence of Aspergillus and Candida species were observed over time in patients treated with several Cayston treatment courses. The clinical significance of this finding is unknown.
No interaction studies have been performed. However, no evidence of any drug interactions with Cayston were identified from clinical studies in which Cayston was taken concomitantly with bronchodilators, dornase alfa, pancreatic enzymes, azithromycin, tobramycin, oral steroids (less than 10 mg daily/20 mg every other day) and inhaled steroids.
Pregnancy
There are no data from the use of aztreonam in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
Systemic concentration of aztreonam following inhaled administration of Cayston is low compared to a standard dose of aztreonam for injection (approximately 1% of the concentration resulting from a dose of 500 mg aztreonam for injection).
Cayston should not be used during pregnancy unless the clinical condition of the woman requires treatment with aztreonam.
Breast-feeding
Following administration of aztreonam for injection, aztreonam is excreted in human milk at very low concentrations. Systemic concentration of aztreonam following inhaled administration of Cayston is approximately 1% of the concentration resulting from a standard dose of aztreonam for injection. Therefore, and because of low oral absorption, aztreonam exposure in breast-fed infants due to mothers receiving Cayston is likely to be extremely low.
Cayston can be used during breast-feeding.
Fertility
Non-clinical data for aztreonam for injection about fertility do not indicate any adverse effects.
No studies on the effects on the ability to drive and use machines have been performed. However, based on the safety profile and mechanism of action, Cayston is not expected to adversely affect the ability to drive or use machines.
a. Summary of the safety profile
The safety of Cayston was evaluated in three Phase 3 studies in 344 predominantly adult patients (77%) with chronic P. aeruginosa. In two Phase 3 placebo-controlled studies patients received Cayston 75 mg 2 times (69 patients) or 3 times a day (146 patients) for 28 days. In one Phase 3 open-label follow-on study 274 CF patients received up to nine 28-day treatment courses of Cayston 75 mg 2 times or 3 times a day.
In the two Phase 3 placebo-controlled clinical studies, the most frequently occurring adverse reactions to Cayston were cough (58%), nasal congestion (18%), wheezing (15%), pharyngolaryngeal pain (13.0%), and pyrexia (12%).
An acute reduction of 1 is a complication associated with nebulised therapies, including Cayston (see section 4.4).
b. Tabulated summary of adverse reactions
The adverse reactions with suspected (at least possible) relationship to treatment in the placebo-controlled studies are listed below by body system organ class and frequency.
Frequencies are defined as follows: very common (
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1 See section c. Description of selected adverse reactions
c. Description of selected adverse reactions
Bronchospasm
Nebulised therapies, including Cayston, may be associated with bronchospasm (an acute reduction of 1). In placebo-controlled studies, bronchospasm was observed in 3% of patients treated with Cayston versus 4% of patients treated with placebo, despite pre-treatment with a bronchodilator before dosing with study treatment (see section 4.4).
Allergic reactions
Rash has been reported with the use of Cayston and may be indicative of an allergic reaction to Cayston (see section 4.4).
The following rare and severe adverse reactions, although these have not been observed to date with Cayston, have been reported after parenteral use of other aztreonam containing products: toxic epidermal necrolysis, anaphylaxis, purpura, erythema multiforme, exfoliative dermatitis, urticaria, petechiae, pruritus, diaphoresis.
Adverse reactions specifically associated with overdose of Cayston have not been identified. Since the plasma concentration of aztreonam following administration of Cayston (75 mg) is approximately 0.6 µg/ml, compared to serum levels of 54 µg/ml following administration of aztreonam for injection (500 mg), no safety issues associated with Cayston overdose are anticipated.
Pharmacotherapeutic group: Antibacterials for systemic use, other beta-lactam antibacterials, ATC code: J01DF01
Mechanism of action
Aztreonam exhibits activity in vitro against gram-negative aerobic pathogens, including P. aeruginosa. Aztreonam binds to penicillin-binding proteins of susceptible bacteria, which leads to inhibition of bacterial cell wall synthesis, followed by filamentation and cell lysis.
Mechanisms of resistance
Loss of susceptibility to aztreonam in CF patients with P. aeruginosa occurs either through selection of strains with mutations located on the chromosome or rarely through acquisition of plasmid/integrin mediated genes.
Known mechanisms of resistance to aztreonam mediated by mutation of chromosomal genes include: hyperexpression of the Class C beta-lactamase AmpC and up-regulation of the efflux pump MexAB-OprM. The known mechanism of resistance to aztreonam mediated by acquisition of genes involves acquisition of extended spectrum beta-lactam enzymes (ESBLs) that hydrolyse the four-member, nitrogen-containing ring of aztreonam.
ESBLs from Class A, B and D beta-lactamases generally have little or no activity against aztreonam. Class A beta-lactamases reported to hydrolyse aztreonam include the VEB type (primarily Southeast Asia), PER type (Turkey), and GES and IBC types (France, Greece, and S. Africa). There are rare reports of organisms with metallo-beta-lactamases (MBLs), Class B, that are resistant to aztreonam, VIM-5 (K. pneumoniae and P. aeruginosa - Turkey), VIM-6 (P. putida - Singapore) and VIM-7 (P. aeruginosa - United States), however, it is possible that these organisms were expressing multiple resistance mechanisms and thus a MBL was not responsible for the observed resistance to aztreonam. There are rare reports of Class D beta-lactamases from clinical isolates of P. aeruginosa, OXA-11 (Turkey) and OXA-45 (United States) that hydrolyse aztreonam.
Microbiology
A single sputum sample from a CF patient may contain multiple isolates of P. aeruginosa and each isolate may have a different level of in vitro susceptibility to aztreonam. The in vitro antimicrobial susceptibility test methods used for parenteral aztreonam therapy can be used to monitor the susceptibility of P. aeruginosa isolated from CF patients.
In the Phase 3 placebo-controlled studies of Cayston, local aztreonam concentrations generally exceeded aztreonam MIC values for P. aeruginosa, regardless of the level of P. aeruginosa susceptibility.
Treatment with a 28-day course of 75 mg 3 times a day Cayston therapy resulted in clinically important improvements in respiratory symptoms, pulmonary function, and sputum P. aeruginosa CFU density, regardless of whether the highest aztreonam MIC for P. aeruginosa was above or below the established susceptibility breakpoint for intravenous aztreonam administration (8 µg/ml). Based on categorical analyses of the relationship between MIC and treatment response, a susceptibility breakpoint for Cayston cannot be established. Over 6 courses of Cayston therapy, P. aeruginosa MIC50 and MIC90 did not change (± 2 dilution change), however there is a theoretical risk that patients treated with Cayston may develop P. aeruginosa isolates resistant to aztreonam or other beta-lactam antibiotics.
In studies of up to six 28-day courses of Cayston therapy, no increases of clinical significance have been observed in the treatment-emergent isolation of other bacterial respiratory pathogens (Stenotrophomonas maltophilia, Alcaligenes xylosoxidans, and Staphylococcus aureus).
Clinical efficacy and safety
Cayston was evaluated over a period of 28-days of treatment (one course) in two randomised, double-blind, placebo-controlled, multicentre studies (CP-AI-005 and CP-AI-007). Patients participating in these studies could subsequently receive multiple courses of Cayston in an open-label follow-on study (CP-AI-006). Entry criteria included CF baseline FEV1 % predicted between 25% and 75% and chronic P. aeruginosa lung infection. Overall, 344 predominantly adult patients (77%) were treated in these studies. Studies were conducted using the Altera Nebuliser System.
CP-AI-007
CP-AI-007 enrolled 164 adult (predominantly) and paediatric patients randomised in a 1:1 ratio comparing inhaled Cayston 75 mg (80 patients) or placebo (84 patients) administered 3 times a day for 28 days (one course). Patients were required to have been off antipseudomonal antibiotics for at least 28 days before treatment with study drug.
Pulmonary function and respiratory symptoms significantly improved from baseline to Day 28 in patients treated with one course of Cayston.
CP-AI-005
CP-AI-005 enrolled 246 adult (predominantly) and paediatric patients. All patients were treated with Tobramycin Nebuliser Solution (TNS) 300 mg, 2 times a day in the four weeks immediately prior to receiving Cayston or placebo either 2 or 3 times a day for 28 days. Patients continued on their baseline medications, including macrolide antibiotics. Patients were randomised in a 2:2:1:1 ratio to be treated with Cayston 75 mg 2 or 3 times a day or volume-matched placebo 2 or 3 times a day for 28 days immediately following the 28-day lead-in course of open-label TNS.
Cayston therapy resulted in significant improvements in pulmonary function and respiratory symptoms at Day 28 in the 66 patients treated with one course Cayston 75 mg 3 times a day.
CP-AI-006
CP-AI-006 was an open-label follow-on study to CP-AI-005 and CP-AI-007 evaluating the safety of repeated exposure to Cayston and the effect on disease-related endpoints over multiple 28-day courses. Patients received Cayston at the same frequency (2 or 3 times a day) as they took Cayston or placebo in the randomised studies. Patients continued on their baseline medications and whenever indicated additional antibiotics were used in the majority of patients to treat exacerbations. Each 28-day course of Cayston was followed by a 28-day off drug period. Over six 28-day courses of therapy, measures of pulmonary function (FEV1), CFQ-R respiratory symptoms scores, and log10P. aeruginosa CFUs showed a trend to improvement while the patients were on treatment compared with off treatment. However, due to the uncontrolled nature of the study and concomitant medications no conclusion can be drawn on the sustainability of the observed short term benefit over subsequent courses of treatment.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Cayston in one or more subsets of the paediatric population in cystic fibrosis patients with Pseudomonas aeruginosa pulmonary infection/colonisation (see section 4.2 for information on paediatric use).
Absorption
Sputum concentrations
Individual patients' sputum aztreonam concentrations exhibited considerable variability. For the combined Phase 3 placebo-controlled studies, ten minutes following a single dose of 75 mg Cayston on Days 0, 14, and 28, the mean sputum concentrations in 195 patients with CF were 726 µg/g, 711 µg/g, and 715 µg/g, respectively, indicating no increased accumulation of aztreonam following repeated dosing.
Plasma concentrations
Individual patients' plasma aztreonam concentrations exhibited considerable variability. One hour following a single dose of 75 mg Cayston (at approximately peak plasma concentration), the mean plasma level in patients with CF was 0.59 µg/ml. Mean peak plasma levels at Days 0, 14, and 28 of a course with 75 mg Cayston 3 times a day were 0.55 µg/ml, 0.67 µg/ml, and 0.65 µg/ml, respectively, indicating no systemic accumulation of aztreonam following 3 times a day dosing. In contrast, the serum concentration of aztreonam following administration of aztreonam for injection (500 mg) is approximately 54 µg/ml.
Elimination
The elimination half-life of aztreonam from serum is approximately 2.1 hours following inhalation administration, similar to what has been reported for aztreonam for injection. Systemically absorbed aztreonam is eliminated by both active tubular secretion and glomerular filtration.
Pharmacokinetics in special populations
Age and gender
There was no clinically relevant effect of age or sex on the pharmacokinetics of Cayston.
Renal and hepatic impairment
Pharmacokinetic studies have not been performed in patients with renal or hepatic impairment.
Pharmacokinetic properties for aztreonam for injection
Peak levels of aztreonam are achieved at about one hour after i.m. administration. After identical single i.m. or i.v. doses, the serum concentrations are comparable at 1 hour (1.5 hours from the start of i.v. infusion), with similar slopes of serum concentrations thereafter. The serum half-life of aztreonam averaged 1.7 hours in subjects with normal renal function, independent of the dose and route. In healthy subjects 60-70% of a single i.m. or i.v. dose was recovered in the urine by 8 hours, and urinary excretion was essentially complete by 12 hours.
A 104-week rat inhalation toxicology study to assess the carcinogenic potential of ascending doses of Cayston demonstrated no drug-related increase in malignant tumours.
Genotoxicity (Chromosomal aberration and mouse lymphoma mutation assay) studies with aztreonam were negative.
Fertility, teratology, perinatal and postnatal studies were conducted with aztreonam for injection in rats at daily doses up to 750 mg/kg without adverse effects. The survival rate during the lactation period was slightly reduced in the offspring of rats that received the highest dose.
Powder vial
L-Lysine
Solvent ampoule
Sodium chloride
Water for injections
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Powder vial: 3 years.
Solvent: 4 years.
After reconstitution, immediate use of Cayston is recommended. If not used immediately, the reconstituted solution must be stored at 2°C - 8°C and used within 8 hours. In-use storage times and conditions prior to use are the responsibility of the user.
Powder vial and solvent ampoule: Store in a refrigerator (2°C - 8°C). May be stored outside a refrigerator but below 25°C for up to 28 days.
For storage conditions of the reconstitued medicinal product, see section 6.3.
Powder vial: Type I amber glass vial with siliconised grey rubber stopper and aluminium tear off overseal.
Solvent: 1 ml low density polyethylene ampoule.
Each 28-day pack of Cayston contains 84 vials of lyophilised Cayston and 88 solvent ampoules. The four additional solvent ampoules are provided in case of spillage.
The following pack sizes are available:
• 28-day pack of Cayston
• Pack containing one 28-day pack of Cayston plus one Altera Nebuliser Handset
Not all pack sizes may be marketed.
Reconstitution
Cayston should only be reconstituted with the solvent provided. Following reconstitution, Cayston is a clear, colourless to slightly coloured solution.
It is recommended that Cayston be administered immediately after reconstitution with solvent. Cayston should not be reconstituted until a dose is ready to be administered. One glass vial containing Cayston is opened by flipping up the metal tab, the metal ring is removed by carefully pulling the tab (tweezers or small pliers may be used to remove the metal ring if necessary) and the grey rubber stopper removed. The liquid is squeezed out of one solvent ampoule into the glass vial. The vial is then gently swirled until contents have completely dissolved. The reconstituted Cayston is then poured into the Altera Nebuliser Handset and the dose administered.
Cayston is administered by inhalation over a 2 to 3 minute period, using an Altera Nebuliser System (consisting of a Cayston specific Altera Nebuliser Handset and Altera Control Unit). Cayston should only be used with the Altera Nebuliser Handset and Altera Aerosol Head connected to an Altera Control Unit or an eFlow rapid Control Unit. Cayston should not be used with any other type of handset or aerosol head. Cayston should not be mixed with any other medicinal products in the Altera Nebuliser Handset. Do not put other medicinal products in the Altera Nebuliser Handset.
Do not reconstitute or mix Cayston with any other solvent or medicinal product. Do not reconstitute more than one dose at a time. Any unused product or waste material should be disposed of in accordance with local requirements.
Gilead Sciences International Limited
Granta Park
Abington
Cambridge
CB21 6GT
United Kingdom
EU/1/09/543/001
EU/1/09/543/002
Date of first authorisation: 21 September 2009
Date of latest renewal: 21 September 2010
09/2011
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
Glycopyrrolate-Neostigmine Injection
Each 1ml of solution contains 0.5mg of glycopyrrolate USP and 2.5mg of neostigmine metilsulfate BP/PhEur.
Clear, colourless sterile solution for injection intended for parenteral administration presented in 1ml clear, type 1, Ph.Eur. glass ampoules.
Reversal of residual non-depolarising (competitive) neuromuscular block.
Glycopyrrolate-Neostigmine injection is for intravenous administration.
Adults and older patients: 1-2 ml intravenously over a period of 10-30 seconds [equivalent to neostigmine metilsulfate 2500 micrograms (2.5mg) with glycopyrrolate 500 micrograms (0.5mg) to neostigmine metilsulfate 5000 micrograms (5mg) with glycopyrrolate 1000 micrograms (1mg)]
Alternatively 0.02mg/kg intravenously over a period of 10-30 seconds may be used [equivalent to neostigmine metilsulfate 50 micrograms/kg (0.05mg/kg) with glycopyrrolate 10 micrograms/kg (0.01mg/kg)].
Children: 0.02ml/kg intravenously over a period of 10-30 seconds [equivalent to neostigmine metilsulfate 50 micrograms/kg (0.05mg/kg) with glycopyrrolate 10 micrograms/kg (0.01mg/kg)].
Alternatively, dilute to l0ml with Water for Injections BP or Sodium Chloride injection BP 0.9% w/v and administer 1ml per 5kg bodyweight.
These doses may be repeated if adequate reversal of neuromuscular blockade is not achieved. Total doses in excess of 2ml are not recommended as this dose of neostigmine may produce depolarising neuromuscular block.
Glycopyrrolate-Neostigmine Injection should not be given to patients with known hypersensitivity to either of the two active ingredients. Glycopyrrolate-Neostigmine Injection should not be given to patients with mechanical obstruction of the gastrointestinal or urinary tracts.
Glycopyrrolate-Neostigmine Injection should not be given in conjunction with suxamethonium as neostigmine potentiates the depolarising myoneural blocking effects of this agent.
Administer with caution to patients with bronchospasm, severe bradycardia or glaucoma. Adrnimstration of anticholinesterase agents to patients with intestinal anastomosis may produce rupture of the anastomosis or leakage of intestinal contents. Although Glycopyrrolate-Neostigmine Injection has been shown to have less impact on the cardiovascular system than atropine with neostigmine metilsulfate, use with caution in patients with coronary artery disease,congestive heart failure, cardiac dysrhythas, hypertension or thyrotoxicosis. Use with caution in patients with epilepsy or Parkinsonism. The product should be used cautiously in pyrexial patients due to inhibition of sweating.
Neostigmine potientates the depolarising myoneural blocking effects of suxamethonium (see contra-indications above).
Reproduction studies in rats and rabbits revealed no teratogenic effects from glycopyrrolate. Safety in human pregnancy and lactation has not been established. However, diminished rates of conception and of survival at weaning were observed in rats, in a dose-related manner. Studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate. The significance of this for man is not clear. The safety of neostigmine metilsulfate in pregnancy and lactation has not been established.
Not relevant as the product is for intra-operative use.
The glycopyrrolate component of Glycopyrrolate-Neostigmine Injection can give rise to dry mouth, difficulty in micturition, cardiac dysrhythmias, disturbances of visual accommodation and inhibition of sweating. The neostigmine component of Glycopyrrolate-Neostigmine Injection can give rise to bradycardia, increased oropharyngeal secretions, cardiac dysrhythmias and increased gastrointestinal activity. If severe neostigmine-induced muscarinic side effects occur (bradycardia, increased oropharyngeal secretions, decreased cardiac conduction rate, bronchospasm or increased gastrointestinal activity etc), these may be treated by the intravenous administration of Glycopyrrolate Injection 200-600 micrograms (0.2-0.6mg) or atropine 400-1200 micrograms (0.4-1.2mg).
The treatment of overdosage depends upon whether signs of anticholinesterase or anticholinergic overdosage are predominant presenting features. Signs of neostigmine overdosage (bradycardia, increased oropharyngeal secretions, bronchospasm etc) may be treated by the administration of Glycopyrrolate Injection 200-600 micrograms (0.2-0.6mg) or atropine 400-1200 micrograms (0.4-1.2mg). In severe cases, respiratory depression may occur and artificial ventilation may be necessary in such patients. Signs of glycopyrrolate overdosage (tachycardia, ventricular irritability etc) may be treated by the administration of neostigmine metilsulfate 1000 micrograms (1.0mg) for each 1000 micrograms (1.0mg) of glycopyrrolate known to have been administered. As glycopyrrolate is a quaternary ammonium agent, symptoms of overdosage are peripheral rather than central in nature; centrally acting anticholinesterase drugs such as physostigmine are therefore unnecessary to treat glycopyrrolate overdosage.
Glycopyrrolate is a quaternary ammonium anticholinergic agent. Glycopyrrolate has a more gradual onset and longer duration of action than atropine. Neostigmine metilsulfate is a quaternary ammonium anticholinesterase. Glycopyrrolate-Neostigmine Injection is associated with less initial tachycardia and better protection against the subsequent cholinergic effects of neostigmine metilsulfate than a mixture of atropine and neostigmine metilsulfate. In addition, residual central anticholinergic effects are minimised due to the limited penetration of Glycopyrrolate into the central nervous system. Administration of glycopyrrolate with neostigmine metilsulfate is associated with greater cardiostability than administration of glycopyrrolate and neostigmine metilsulfate separately.
Glycopyrrolate-Neostigmine Injection can be used when atropine has been used as a preoperative anticholinergic.
Glycopyrrolate is a quaternary ammonium anti-muscarinic agent. The quaternary ammonium moiety renders glycopyrrolate highly ionised at physiological pH and it thus penetrates the blood brain and placental barriers poorly. Excretion is through bile and urine as unchanged drug.
Neostigmine metilsulfate is a quaternary ammonium anticholinesterase. Neostigmine undergoes hydrolysis by cholinesterases and is also metabolised in the liver. It is rapidly eliminated and is excreted in the urine both as unchanged drug and metabolites.
No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.
Disodium Hydrogen Phosphate Dodecahydrate BP/PhEur.
Citric Acid Monohydrate BP/Ph.Eur.
Sodium Hydroxide BPI Ph.Eur.
Water for Injections BPI Ph.Eur.
Do not mix Glycopyrrolate Neostigmine Injection with any other product.
2 years.
Store below 25°C. Protect from light.
Glycopyrrolate Neostigmine Injection is presented in clear glass ampoules packed in cardboard cartons to contain 5 or 10 ampoules.
Keep out of reach of children.
If only part of an ampoule is used, discard the remaining solution.
ADMINISTRATIVE DETAILS
Antigen International Ltd.
Roscrea
Co. Tipperary
Ireland.
PL 02848/0200
3 March 1998
29 January 1998
Prop.INN
0000154-82-5
C28-H38-N2-O6
498
Analgesic
1,4-bis[(2-methoxy-4-propylphenoxy)acetyl]piperazine (WHO)
Piperazine, 1,4-bis((2-methoxy-4-propylphenoxy)acetyl)-
International Drug Name Search
Glossary
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| Prop.INN | Proposed International Nonproprietary Name (World Health Organization) |
| WHO | World Health Organization |
Stadmed Ethacid may be available in the countries listed below.
Etamsylate is reported as an ingredient of Stadmed Ethacid in the following countries:
International Drug Name Search
Diclostar PF may be available in the countries listed below.
Diclofenac sodium salt (a derivative of Diclofenac) is reported as an ingredient of Diclostar PF in the following countries:
International Drug Name Search
Couren may be available in the countries listed below.
Captopril is reported as an ingredient of Couren in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
Rec.INN
0000065-29-2
C30-H60-I3-N3-O3
891
Muscle relaxant, peripherally acting
Ethanaminium, 2,2',2''-[1,2,3-benzenetriyltris(oxy)]tris[N,N,N-triethyl-, triiodide
International Drug Name Search
Glossary
| BANM | British Approved Name (Modified) |
| DCF | Dénomination Commune Française |
| IS | Inofficial Synonym |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
Enalapril / Hydrochloorthiazide PCH may be available in the countries listed below.
Enalapril maleate (a derivative of Enalapril) is reported as an ingredient of Enalapril / Hydrochloorthiazide PCH in the following countries:
Hydrochlorothiazide is reported as an ingredient of Enalapril / Hydrochloorthiazide PCH in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
In the US, Vitamin K1 (phytonadione systemic) is a member of the drug class vitamins and is used to treat Hypoprothrombinemia - Anticoagulant Induced, Hypoprothrombinemia - Not Associated with Anticoagulant Therapy, Hypoprothrombinemia - Prophylaxis and Vitamin K Deficiency.
US matches:
Phytomenadione is reported as an ingredient of Vitamin K1 in the following countries:
International Drug Name Search
PreviDent®5000ppm
DRY MOUTH1 Rx ONLY
1.1% Sodium Fluoride
Prescription Strength Toothpaste
Self-topical neutral fluoride toothpaste containing 1.1% (w/w) sodium fluoride for use as a dental caries preventative in adults and pediatric patients.
Sodium fluoride 1.1% (w/w)
water, sorbitol, hydrated silica, propylene glycol, glycerin, PEG-40 hydrogenated castor oil, dipotassium phosphate, poloxamer 407, flavor, PVM/MA copolymer, xanthan gum, sodium benzoate, sodium hydroxide, sodium saccharin, cocamidopropyl betaine, cetylpyridinium chloride, potassium sorbate, pectin, FD&C blue no. 1
Frequent topical applications to the teeth with preparations having a relatively high fluoride content increase tooth resistance to acid dissolution and enhance penetration of the fluoride ion into tooth enamel.
A dental caries preventive; for once daily self-applied topical use. It is well established that 1.1% sodium fluoride is safe and extraordinarily effective as a caries preventive when applied frequently with mouthpiece applicators.1-4 PreviDent® 5000 Dry Mouth brand of 1.1% sodium fluoride toothpaste in a squeeze bottle is easily applied onto a toothbrush. This prescription toothpaste should be used once daily in place of your regular toothpaste unless otherwise instructed by your dental professional. May be used in areas where drinking water is fluoridated since topical fluoride cannot produce fluorosis. (See WARNINGS for exception.)
Do not use in pediatric patients under age 6 years unless recommended by a dentist or physician.
Prolonged daily ingestion may result in various degrees of dental fluorosis in pediatric patients under age 6 years, especially if the water fluoridation exceeds 0.6 ppm, since younger pediatric patients frequently cannot perform the brushing process without significant swallowing. Use in pediatric patients under age 6 years requires special supervision to prevent repeated swallowing of toothpaste which could cause dental fluorosis. Pediatric patients under age 12 should be supervised in the use of this product. Read directions carefully before using. Keep out of reach of infants and children.
Not for systemic treatment. DO NOT SWALLOW.
In a study conducted in rodents, no carcinogenesis was found in male and female mice and female rats treated with fluoride at dose levels ranging from 4.1 to 9.1 mg/kg of body weight. Equivocal evidence of carcinogenesis was reported in male rats treated with 2.5 and 4.1 mg/kg of body weight. In a second study, no carcinogenesis was observed in rats, males or females, treated with fluoride up to 11.3 mg/kg of body weight. Epidemiological data provide no credible evidence for an association between fluoride, either naturally occurring or added to drinking water, and risk of human cancer.
Fluoride ion is not mutagenic in standard bacterial systems. It has been shown that fluoride ion has potential to induce chromosome aberrations in cultured human and rodent cells at doses much higher than those to which humans are exposed. In vivo data are conflicting. Some studies report chromosome damage in rodents, while other studies using similar protocols report negative results.
Potential adverse reproductive effects of fluoride exposure in humans has not been adequately evaluated. Adverse effects on reproduction were reported for rats, mice, fox, and cattle exposed to 100 ppm or greater concentrations of fluoride in their diet or drinking water. Other studies conducted in rats demonstrated that lower concentrations of fluoride (5 mg/kg of body weight) did not result in impaired fertility and reproductive capabilities.
It has been shown that fluoride crosses the placenta of rats, but only 0.01% of the amount administered is incorporated in fetal tissue. Animal studies (rats, mice, rabbits) have shown that fluoride is not a teratogen. Maternal exposure to 12.2 mg fluoride/kg of body weight (rats) or 13.1 mg/kg of body weight (rabbits) did not affect the litter size or fetal weight and did not increase the frequency of skeletal or visceral malformations. There are no adequate and well-controlled studies in pregnant women. However, epidemiological studies conducted in areas with high levels of naturally fluoridated water showed no increase in birth defects. Heavy exposure to fluoride during in utero development may result in skeletal fluorosis which becomes evident in childhood.
It is not known if fluoride is excreted in human milk. However, many drugs are excreted in milk, and caution should be exercised when products containing fluoride are administered to a nursing woman. Reduced milk production was reported in farm-raised fox when the animals were fed a diet containing a high concentration of fluoride (98-137 mg/kg of body weight). No adverse effects on parturition, lactation, or offspring were seen in rats administered fluoride up to 5 mg/kg of body weight.
The use of PreviDent® 5000 Dry Mouth in pediatric age groups 6 to 16 years as a caries preventive is supported by pioneering clinical studies with 1.1% sodium fluoride gels in mouth trays in students age 11 to 14 years conducted by Englander et al. 2-4 Safety and effectiveness in pediatric patients below the age of 6 years have not been established. Please refer to the CONTRAINDICATIONS and WARNINGS sections.
Of the total number of subjects in clinical studies of 1.1% (w/v) sodium fluoride, 15 percent were 65 and over, while 1 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.5
Allergic reactions and other idiosyncrasies have been rarely reported.
Accidental ingestion of large amounts of fluoride may result in acute burning in the mouth and sore tongue. Nausea, vomiting, and diarrhea may occur soon after ingestion (within 30 minutes) and are accompanied by salivation, hematemesis, and epigastric cramping abdominal pain. These symptoms may persist for 24 hours. If less than 5 mg fluoride/kg body weight (i.e., less than 2.3 mg fluoride/lb body weight) have been ingested, give calcium (e.g., milk) orally to relieve gastrointestinal symptoms and observe for a few hours. If more than 5 mg fluoride/kg body weight (i.e., more than 2.3 mg fluoride/lb body weight) have been ingested, induce vomiting, give orally soluble calcium (e.g., milk, 5% calcium gluconate or calcium lactate solution) and immediately seek medical assistance. For accidental ingestion of more than 15 mg fluoride/kg of body weight (i.e., more than 6.9 mg fluoride/lb body weight), induce vomiting and admit immediately to a hospital facility.
A treatment dose (a thin ribbon) of PreviDent® 5000 Dry Mouth contains approximately 2.5 mg fluoride. A 3.4 FL OZ (100 mL) bottle contains approximately 610 mg fluoride.
Follow these instructions unless otherwise instructed by your dental professional:
3.4 FL OZ (100 mL) in plastic bottles. Soothing Mint: NDC 0126-0016-61
Store at Controlled Room Temperature, 68-77°F (20-25°C)
Questions? Comments? Please Call 1-800-962-2345
www.colgateprofessional.com
Colgate Oral Pharmaceuticals, Inc.
a subsidiary of Colgate-Palmolive Company
New York, NY 10022 U.S.A.
Rev. 11/08 P10001050
NDC 0126-0016-61
Colgate®
PreviDent®
5000ppm
DRY MOUTH*
1.1% Sodium Fluoride
*Formulated for Dry Mouth Sufferers
PRESCRIPTION STRENGTH
TOOTHPASTE
SLS Free Formula
SOOTHING MINT
3.4 FL OZ (100 mL)
Rx ONLY
| PREVIDENT 5000 DRY MOUTH sodium fluoride gel, dentifrice | ||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| Unapproved drug other | 07/06/2009 | ||
| Labeler - Colgate-Palmolive Company (055002195) |
