Nitroglycerin Injection USP 0.05% w / v, 10ml

1. Name Of The Medicinal Product

Nitroglycerin Injection U.S.P. 0.05% w/v, 10ml

2. Qualitative And Quantitative Composition

Each 10ml contains 5mg of Nitroglycerin U.S.P.

3. Pharmaceutical Form

Clear, colourless or pale yellow sterile solution intended for parenteral administration to human beings after dilution in either Sodium Chloride Injection B.P. or Glucose Injection B.P.

4. Clinical Particulars

4.1 Therapeutic Indications

a) Control of blood pressure in perioperative hypertension, i.e. hypertension associated with surgical procedures, especially cardiovascular procedures and in the immediate post-surgical period.

b) Unresponsive congestive cardiac failure secondary to acute myocardial infarction.

c) Treatment of angina pectoris in patients who have not responded to recommended doses of organic nitrates and/or beta-adrenoceptor blocking agents.

d) Production of elective hypotension and maintenance of controlled hypotension during surgical procedures.

4.2 Posology And Method Of Administration

Route of administration: Intravenous infusion after dilution.

Nitroglycerin Injection is a concentrated potent drug which must be diluted in either Sodium Chloride Injection B.P. or Glucose Injection B.P. prior to its infusion.

Nitroglycerin Injection should not be mixed with other drugs. It is recommended that the drug is diluted to give a final concentration of 400 micrograms/ml or less, according to the dosage requirements of the patient. Most patients respond to doses between 10 - 200 micrograms/minute, although doses up to 400 micrograms/minute may be required during some surgical procedures.

Dosage: The usual recommended dose range is 10 - 200 micrograms/minute. Doses in excess of these have been used and up to 400 micrograms/minute may be required during some surgical procedures. Careful clinical assessment and frequent monitoring of blood pressure and heart rate are essential to maintain the appropriate rate of infusion. Where available, monitoring of pulmonary capillary wedge pressure and cardiac output can be used to titrate dosage to response.

Surgery: For the control of hypertensive episodes, the recommended starting dose is 25 micrograms/minute increasing in steps of 25 micrograms/minute at 5 minute intervals until the desired reduction in blood pressure is achieved. Although most patients respond to doses between 10 to 200 micrograms/minute, doses up to 400 micrograms/minute have been required during some surgical procedures. In the treatment of perioperative myocardial ischaemia, the recommended starting dose is 15 to 20 micrograms/minute increasing in steps of 10 to 15 micrograms/minute until the desired effect is achieved.

Unresponsive congestive cardiac failure secondary to acute myocardial infarction: The recommended starting dose is 20 to 25 micrograms/minute which can be decreased to 10 micrograms/minute or increased in steps of 20 to 25 micrograms/minute at 15 to 30 minute intervals until the desired effect is achieved.

Unstable angina : The recommended starting dose is 10 micrograms/minute increasing in steps of 5 to 10 micrograms/minute at approximately 30 minute intervals.

Children: The safety and effectiveness of nitroglycerin in children have not been established.

Use in the elderly : Special care in dose titration and monitoring is required in elderly patients, as there is an increased risk of a fall in perfusion pressure owing to a higher prevalence of coronary or cerebral artery disease in the elderly.

4.3 Contraindications

Known hypersensitivity to organic nitrates. Marked anaemia, raised intracranial pressure (e.g. due to head trauma or cerebral haemorrhage), uncorrected hypovolaemia or severe hypotension. Constrictive pericarditis and pericardiac tamponade.

The hypotensive effects of nitrates are potentiated by sildenafil, and their co-administration is contra-indicated.

4.4 Special Warnings And Precautions For Use

Nitroglycerin Injection should be used with caution in patients suffering from severe hepatic or renal disease, hypothyroidism, malnutrition, hypothermia and in those predisposed to closed angle glaucoma.

In order to achieve and maintain the correct dosage, continuous monitoring of physiological parameters must be performed, including blood pressure and heart rate in all patients and other measurements such as capillary wedge pressure as appropriate. The systemic blood pressure and coronary perfusion pressure must be maintained adequately at all times.

Nitroglycerin Injection should be administered by means of a micro-drip set infusion pump or similar device which permits maintenance of a constant infusion rate. The giving set should be composed of glass or rigid polyethylene. Infusion systems composed of PVC may absorb up to 50% of the nitroglycerin from solution, resulting in reduced potency of the infusion (see incompatibilities).

Excessive hypotension, especially for prolonged periods of time, must be avoided because of the possible deleterious effects of poor perfusion on body organs and the consequent risk of ischaemic damage.

Paradoxical bradycardia and increased angina pectoris may accompany nitroglycerin induced hypotension.

Patients with normal or low left ventricular filling pressure or pulmonary capillary wedge pressure are especially sensitive to the hypotensive effects of intravenous nitroglycerin and may respond fully to doses as small as 5 micrograms/minute. Where pulmonary capillary wedge pressure is being monitored, it will be noted that a fall in wedge pressure precedes the onset of arterial hypotension. Therefore, pulmonary capillary wedge pressure is a useful guide to titration of the drug in these circumstances.

Nitroglycerin Injection contains both alcohol and propylene glycol.

Safety for intracoronary injection has not been shown.

Propylene glycol can lead to lacticacidosis and it is recommended that the duration of therapy with this product be restricted to no more than three successive days.

There are no long-term studies to evaluate the carcinogenic potential of nitroglycerin

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Nitroglycerin may potentiate the hypotensive effect of other anti-hypertensive agents. The hypotensive effects of nitrates are potentiated by sildenafil (see Contra-indications).

4.6 Pregnancy And Lactation

There is inadequate evidence of the safety of nitroglycerin in pregnancy and lactation.

Nitroglycerin Injection should not be used during pregnancy or lactation unless considered essential by the physician.

4.7 Effects On Ability To Drive And Use Machines

The indications for Nitroglycerin Injection limit its use to situations in which there would not be an opportunity to drive or to operate machinery.

4.8 Undesirable Effects

Adverse reactions to nitroglycerin may include hypotension, tachycardia, headache, nausea, vomiting, restlessness, dizziness, muscle twitching, palpitation, paradoxical bradycardia, retrosternal discomfort and abdominal pain.

4.9 Overdose

Accidental overdosage may result in severe hypotension and reflex tachycardia which can be managed by elevating the lower limbs and decreasing or temporarily withdrawing the infusion until the condition is stabilised. In extreme states of hypotension, intravenous administration of an alpha adrenergic agonist such as methoxamine hydrochloride or phenylephrine hydrochloride should be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Nitroglycerin is an organic nitrate. Relaxation of vascular smooth muscle is the principal pharmacological action of nitroglycerin. Nitroglycerin causes dilatation of both venous and arterial smooth muscle in a dose-related manner. Venodilatation predominates at lower infusion rates and, as the infusion rate increases, nitroglycerin dilates both arterial and venous systems. Pulmonary vascular resistance, systemic vascular resistance and arterial pressure are all reduced by administration of intravenous nitroglycerin.

Dilatation of the post-capillary vessels promotes peripheral pooling of blood and decreases venous return, reducing left ventricular end-diastolic pressure (pre-load). Relaxation of arterioles reduces systemic vascular resistance and arterial pressure (after-load).

Myocardial oxygen consumption (as measured by the rate-pressure product and tension-time index) is decreased by both the venous and arterial effects of nitroglycerin, and a more favourable supply-demand ratio can be achieved. Although the predominant clinical benefits result from the peripheral vasodilating effects and the resultant decrease in myocardial oxygen demand, some effect on oxygen supply may occur by direct coronary vasodilatation. Redistribution of blood from normal to ischaemic areas of the myocardium has been demonstrated.

5.2 Pharmacokinetic Properties

Pharmacokinetic data for intravenous nitroglycerin are difficult to interpret due to factors such as the variation in sensitivity of assay procedures for calculating plasma concentrations of the drug, intersubject variation in plasma concentrations and adsorption of nitroglycerin by some types of giving sets. There appears to be no close correlation between the infusion rates of intravenous nitroglycerin and the blood concentrations achieved.

Nitroglycerin is extensively distributed and is rapidly metabolised in the liver and erythrocytes by the enzyme glutathione - organic nitrate reductase. The enzyme converts nitroglycerin to dinitrates, mononitrates and inorganic nitrites, which have about one tenth of the vasodilating activity of nitroglycerin and which are excreted in the urine within 24 hours after a single dose. The elimination half-life of nitroglycerin ranges from less than one minute to three minutes. Impaired hepatic function may impair the clearance of the drug.

5.3 Preclinical Safety Data

No further relevant information other than that which is contained in the other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene Glycol B.P.

Ethanol B.P.

Water for Injections B.P.

6.2 Incompatibilities

Nitroglycerin Injection is compatible with glass infusion bottles. It has been shown to be compatible with certain rigid infusion packs made of polyethylene, such as the polyfusor from Kendall or bottlepak and flatpak from Braun, Dublin. The injection can be administered as an infusion using one of these recommended infusion bottles/packs.

Nitroglycerin Injection is not compatible with infusion bags made from polyvinyl chloride (PVC) and over 40% of the nitroglycerin activity can be lost if contact with PVC is prolonged. Therefore, it is recommended that contact with PVC bags is avoided. Some loss of activity can also occur through the infusion sets but the clinical response should be used to determine the rate of infusion and thus the dosage of the drug required by the patient.

Alternatively, nitroglycerin injection may be infused slowly via a syringe pump using a glass syringe or rigid plastic syringe (Gillette Sabre syringe, Brunswick Disposable, B.D.

Plastipak syringes). A high pressure polyethylene tubing known to be compatible with nitroglycerin is the Lectrocath tubing, Vygon, Gloucester.

6.3 Shelf Life

3 years (36 months).

If only part of an ampoule is used, discard the remaining solution.

6.4 Special Precautions For Storage

Protect from light.

Store in a cool dry place.

6.5 Nature And Contents Of Container

10ml, clear glass ampoules, glass type 1 Ph. Eur., packed in cardboard cartons to contain 5 x 10ml or 10 x 10ml ampoules.

6.6 Special Precautions For Disposal And Other Handling

For administration by i.v. infusion only after dilution with a suitable vehicle such as 5% dextrose in water or 0.9% w/v sodium chloride.

Use as directed by the physician.

Keep out of reach of children.

If only part used, discard the remaining solution.

7. Marketing Authorisation Holder

Antigen International Ltd.,

Roscrea,

Co. Tipperary,

Ireland.

8. Marketing Authorisation Number(S)

PL 2848/0167.

9. Date Of First Authorisation/Renewal Of The Authorisation

29 November 1991.

10. Date Of Revision Of The Text

April 1999

Tambocor XL 200mg Capsules

1. Name Of The Medicinal Product

Tambocor^tm XL 200mg capsules

2. Qualitative And Quantitative Composition

Each capsule contains flecainide acetate 200mg

For excipients see 6.1

3. Pharmaceutical Form

Prolonged release capsule hard.

Size 1 hard gelatin capsule with light grey cap and opaque pink body with 3M 200 printed in black ink.

4. Clinical Particulars

4.1 Therapeutic Indications

Tambocor is a potent sodium channel blocking agent for the treatment of the conditions listed below:

The effect on the JT interval is insignificant at therapeutic levels.

Tambocor XL capsules are indicated for:

a) AV nodal reciprocating tachycardia, arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways.

b) Paroxysmal atrial fibrillation in patients with disabling symptoms when treatment need has been established and in the absence of left ventricular dysfunction (see 4.4, Special warnings and precautions for use).

Arrhythmias of recent onset will respond more readily. Tambocor XL capsules can be used for the maintenance of normal rhythm following conversion by other means.

Tambocor XL capsules are for oral administration.

4.2 Posology And Method Of Administration

The controlled-release form of flecainide acetate is administered as a once-daily dose. Tambocor XL should not be used for control of arrhythmias in acute situations. Treatment should be initiated with either Intravenous or oral Tambocor IR formulations then switched to Tambocor XL.

Adults: Supraventricular arrhythmias: The recommended starting dosage is 50mg twice daily (IR formulation) and most patients will be controlled at this dose. If required the dose may be increased to a maximum of 300mg (IR formulation) daily.

Those patients controlled on 200mg (IR) daily may be switched to one 200mg XL capsule once daily. After 3-5 days it is recommended that the dosage be progressively adjusted to the lowest level which maintains control of the arrhythmia. It may be possible to reduce dosage during long-term treatment.

Children: Tambocor is not recommended in children under 12, as there is insufficient evidence of its use in this age group.

Elderly Patients: The rate of flecainide elimination from plasma may be reduced in elderly people. This should be taken into consideration when making dose adjustments.

Plasma levels: Based on PVC suppression, it appears that plasma levels of 200 – 1000ng/ml may be needed to obtain the maximum therapeutic effect. Plasma levels above 700 – 1000ng/ml are associated with increased likelihood of adverse experiences.

Dosage in impaired renal function: In patients with significant renal impairment (creatinine clearance of 35ml/min/1.73 sq.m. or less) the maximum initial dosage should be 100mg IR daily. When used in such patients, frequent plasma level monitoring is strongly recommended.

It is recommended that intravenous treatment with Tambocor should be administered in hospital.

Treatment with Tambocor XL should be under direct hospital or specialist supervision for patients with:

a) AV nodal reciprocating tachycardia; arrhythmias associated with Wolff-Parkinson-White Syndrome and similar conditions with accessory pathways.

b) Paroxysmal atrial fibrillation in patients with disabling symptoms.

Treatment for patients with other indications should continue to be initiated in hospital.

4.3 Contraindications

Tambocor is contra-indicated in cardiac failure and in patients with a history of myocardial infarction who have either asymptomatic ventricular ectopics or asymptomatic non-sustained ventricular tachycardia.

It is also contra-indicated in patients with long standing atrial fibrillation in whom there has been no attempt to convert to sinus rhythm, and in patients with haemodynamically significant valvular heart disease.

Unless pacing rescue is available, Tambocor should not be given to patients with sinus node dysfunction, atrial conduction defects, second degree or greater atrio-ventricular block, bundle branch block or distal block.

4.4 Special Warnings And Precautions For Use

Electrolyte disturbances should be corrected before using Tambocor.

Since flecainide elimination from the plasma can be markedly slower in patients with significant hepatic impairment, flecainide should not be used in such patients unless the potential benefits clearly outweigh the risks. Plasma level monitoring is strongly recommended in these circumstances.

Tambocor is known to increase endocardial pacing thresholds – i.e. to decrease endocardial pacing sensitivity. This effect is reversible and is more marked on the acute pacing threshold than on the chronic. Tambocor should thus be used with caution in all patients with permanent pacemakers or temporary pacing electrodes, and should not be administered to patients with existing poor thresholds or non-programmable pacemakers unless suitable pacing rescue is available.

Generally a doubling of either pulse width or voltage is sufficient to regain capture, but it may be difficult to obtain ventricular thresholds less than 1 Volt at initial implantation in the presence of Tambocor.

The minor negative inotropic effect of flecainide may assume importance in patients predisposed to cardiac failure. Difficulty has been experienced in defibrillating some patients. Most of the cases reported had pre-existing heart disease with cardiac enlargement, a history of myocardial infarction, arterio-sclerotic heart disease and cardiac failure.

Tambocor should be avoided in patients structural organic heart disease or abnormal left ventricular function.

Tambocor should be used with caution in patients with acute onset of atrial fibrillation following cardiac surgery.

In a large scale, placebo-controlled clinical trial in post-myocardial infarction patients with asymptomatic ventricular arrhythmia, oral flecainide was associated with a 2.2 fold higher incidence of mortality or non-fatal cardiac arrest as compared with its matching placebo. In that same study, an even higher incidence of mortality was observed in flecainide-treated patients with more than one myocardial infarction. Comparable placebo-controlled clinical trials have not been done to determine if flecainide is associated with higher risk of mortality in other patient groups.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Flecainide is a class I anti-arrhythmic and interactions are possible with other anti-arrhythmic drugs where additive effects may occur or where drugs interfere with the metabolism of flecainide. The following known categories of drugs may interact with flecainide:

Cardiac glycosides: Flecainide can cause the plasma digoxin level to rise by about 15%, which is unlikely to be of clinical significance for patients with plasma levels in the therapeutic range. It is recommended that the digoxin plasma level in digitalised patients should be measured not less than six hours after any digoxin dose, before or after administration of flecainide.

Class II anti-arrhythmics: the possibility of additive negative inotropic effects of beta-blockers and other cardiac depressants with flecainide should be recognised.

Class III anti-arrhythmics: when flecainide is given in the presence of amiodarone, the usual flecainide dosage should be reduced by 50% and the patient monitored closely for adverse effects. Plasma level monitoring is strongly recommended in these circumstances.

Class IV anti-arrhythmics: use of flecainide with other sodium channel blockers is not recommended.

Anti-depressants: fluoxetine increases plasma flecainide concentration, increased risk of arrhythmias with tricyclics, manufacturer of reboxetine advises caution.

Anti-epileptics: limited data in patients receiving known enzyme inducers (phenytoin, phenobarbital, carbamazepine) indicate only a 30% increase in the rate of flecainide elimination.

Anti-psychotics: clozapine– increased risk of arrhythmias.

Anti-histamines: increased risk of ventricular arrhythmias with mizolastine and terfenadine (avoid concomitant use).

Anti-malarials: quinine increases plasma concentration of flecainide.

Antivirals: plasma concentration increased by ritonavir, lopinavir and indinavir (increased risk of ventricular arrhythmias, avoid concomitant use).

Diuretics: Class effect due to hypokalaemia giving rise to cardiac toxicity.

Ulcer healing drugs: cimetidine inhibits metabolism of flecainide. In healthy subjects receiving cimetidine (1g daily) for one week, plasma flecainide levels increased by about 30% and the half-life increased by about 10%.

Anti-smoking aids: Co-administration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including flecainide, should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving flecainide, the need to decrease the dose of the original medication should be considered.

Treatment with Tambocor is compatible with use of oral anti-coagulants.

4.6 Pregnancy And Lactation

There is no evidence as to drug safety in human pregnancy. In New Zealand White rabbits high doses of flecainide caused some foetal abnormalities, but these effects were not seen in Dutch Belted rabbits or rats. The relevance of these findings to humans has not been established. Data have shown that flecainide crosses the placenta to the foetus in patients taking flecainide during pregnancy.

Flecainide is excreted in human milk and appears in concentrations which reflect those in maternal blood. The risk of adverse effects to the nursing infant is very small.

4.7 Effects On Ability To Drive And Use Machines

No effect.

4.8 Undesirable Effects

Body as a Whole: Asthenia, fatigue, fever, oedema

Cardiovascular: Pro-arrhythmic effects occur but are most likely in patients with structural heart disease and/or significant left ventricular impairment.

In patients with atrial flutter the use of Tambocor has been associated with 1:1 AV conduction following initial atrial slowing with resultant ventricular acceleration. This has been seen most commonly following the use of the injection for acute conversion. This effect is usually short lived and abates quickly following cessation of therapy.

The following adverse effects have also been reported.

AV block-second-degree and third degree, bradycardia, cardiac failure/congestive cardiac failure, chest pain, hypotension, myocardial infarction, palpitation and sinus pause or arrest and tachycardia (AT or VT).

Skin and Appendages: A range of allergic skin reactions have been reported including rashes and rare but serious reports of urticaria. There have also been isolated cases of photosensitivity.

Immune System: A small number of cases of increases in anti-nuclear antibodies have been reported, with and without systemic inflammatory involvement.

Haematological: Reductions in red blood cells, white blood cells and platelets have been occasionally reported. These changes are usually mild.

Psychiatric: Rarely, hallucinations, depression, confusion, amnesia. Anxiety and insomnia have been reported

Gastrointestinal: Occasionally nausea and vomiting. The following have also been reported: abdominal pain, anorexia, constipation, diarrhoea, dyspepsia and flatulence (bloating).

Liver and Biliary System: A number of cases of elevated liver enzymes and jaundice have been reported in association with Tambocor treatment. So far this has always been reversible on stopping treatment. Hepatic dysfunction has also been reported.

Neurological: Most commonly giddiness, dizziness and lightheadedness, which are usually transient. Rare instances of dyskinesia have been reported, which have improved on withdrawal of flecainide therapy. Rare instances of convulsions, and during long term therapy a few cases of peripheral neuropathy; paraesthesia and ataxia have been reported. There also have been reports of flushing, headache, hypoaesthesia, increased sweating, somnolence, syncope, tinnitus, tremor and vertigo.

Ophthalmological: Visual disturbances, such as double vision and blurring of vision may occur but these are usually transient and disappear upon continuing or reducing the dosage.

Extremely rare cases of corneal deposits have also been reported.

Respiratory: Dyspnoea and rare cases of pneumonitis have been reported

4.9 Overdose

Overdosage with flecainide is a potentially life threatening medical emergency. No specific antidote is known. There is no known way of rapidly removing flecainide from the system, but forced acid diuresis may theoretically be helpful. Neither dialysis nor haemoperfusion is helpful and injections of anticholinergics are not recommended.

Treatment may include therapy with an inotropic agent, intravenous calcium, giving circulatory assistance (e.g. balloon pumping), mechanically assisting respiration, or temporarily inserting a transvenous pacemaker if there are severe conduction disturbances or the patient's left ventricular function is otherwise compromised.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Tambocor is a Class 1 anti-arrhythmic (local anaesthetic) agent.

Tambocor slows conduction through the heart, having its greatest effect on His Bundle conduction. It also acts selectively to increase anterograde and particularly retrograde accessory pathway refractoriness. Its actions may be reflected in the ECG by prolongation of the PR interval and widening of the QRS complex. The effect on the JT interval is insignificant.

5.2 Pharmacokinetic Properties

Tambocor XL capsules contain polymer-coated microgranules, allowing controlled release of the active substance. Each microgranule constitutes a controlled release form of flecainide acetate, allowing prolongation of the absorption time without modifying the elimination parameters.

Absorption of flecainide acetate via the oral route is greater than 80% of the dose administered.

After administration of one XL capsule, plasma flecainide concentrations gradually increase after a lag time of 2 to 3 hours to reach a peak between the 21^st and 25^th hour and remain at plateau levels until after the 30^th hour.

Absorption of flecainide acetate from capsules is not modified by food.

Steady-state is reached after five days of treatment with minimal fluctuations, and 50% flattening of plasma concentration peaks compared to the tablet form.

Flecainide acetate is widely and rapidly distributed in the tissues. The mean volume of distribution is 8.31 l/kg. Protein binding is low (about 40%).

Flecainide acetate is essentially eliminated in the urine: 25% of the dose is eliminated after 24 hours in the unchanged form. Haemodialysis does not appear to be an effective way to eliminate flecainide acetate. Flecainide acetate is also eliminated by metabolism, especially via the cytochrome 2D6 pathway. The apparent plasma elimination half-life is about 12 to 27 hours, it is not modified with the XL capsule form.

No enzyme induction or inhibition phenomena have been observed after prolonged dosing.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars

6.1 List Of Excipients

Excipients:

Microcrystalline Cellulose

Methacrylic acid-methyl methacrylate (1:2) copolymer

Macrogol 400

Talc

Capsule shell:

Gelatin

Titanium Dioxide (E171)

Iron Oxide Black (E172)

Erythrosine (E127)

Printing ink contains:

Shellac (E904)

Propylene glycol (E1520)

Iron Oxide Black (E172)

6.2 Incompatibilities

None known

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C. Store in original package.

6.5 Nature And Contents Of Container

UPVC/PVDC/Aluminium blister packs containing 15, 30 or 60 capsules.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

United Kingdom

8. Marketing Authorisation Number(S)

PL 15142/0076

9. Date Of First Authorisation/Renewal Of The Authorisation

28^th April 2005

10. Date Of Revision Of The Text

1^st December 2009

Joint

Joint may be available in the countries listed below.

Ingredient matches for Joint

Oxaceprol

Oxaceprol is reported as an ingredient of Joint in the following countries:

• Argentina

International Drug Name Search

Testred

Generic Name: methyltestosterone (METH il tes TOS te role)

Brand Names: Android, Methitest, Testred

What is Testred (methyltestosterone)?

Methyltestosterone is a man-made form of testosterone, a naturally occurring sex hormone that is produced in a man's testicles. Small amounts of testosterone are also produced in a woman's ovaries and adrenal system.

Methyltestosterone is used in men and boys to treat conditions caused by a lack of this hormone, such as delayed puberty or other hormonal imbalances. Methyltestosterone is also used in women to treat breast cancer that has spread to other parts of the body.

Methyltestosterone may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Testred (methyltestosterone)?

Methyltestosterone can cause birth defects. Do not use if you are pregnant. Use effective birth control, and tell your doctor if you become pregnant during treatment. You should not use this medication if you are allergic to methyltestosterone, or have prostate cancer or male breast cancer.

Before receiving methyltestosterone, tell your doctor if you have benign prostatic hypertrophy, breast cancer, a bleeding or blood clotting disorder, liver or kidney disease, heart disease, coronary artery disease, congestive heart failure, or a history of heart attack.

To be sure this medication is helping your condition, your blood will need to be tested on a regular basis. Do not miss any scheduled visits to your doctor.

Methyltestosterone can affect bone growth in boys who are treated for delayed puberty. Bone development may need to be checked with x-rays every 6 months during treatment.

What should I discuss with my health care provider before taking Testred (methyltestosterone)?

You should not use this medication if you are allergic to methyltestosterone, or have certain conditions. Be sure your doctor knows if you have:

• 
  

  prostate cancer;

  
  


• 
  

  male breast cancer; or

  
  


• 
  

  if you are pregnant.

  
  

Before receiving methyltestosterone, tell your doctor if you are allergic to any drugs, or if you have:

• 
  

  benign prostatic hypertrophy (BPH);

  
  


• 
  

  breast cancer;

  
  


• 
  

  a bleeding or blood clotting disorder;

  
  


• 
  

  delayed puberty;

  
  


• 
  

  liver or kidney disease; or

  
  


• 
  

  heart disease, coronary artery disease (hardened arteries), congestive heart failure, or a history of heart attack.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely take methyltestosterone.

FDA pregnancy category X. This medication can cause birth defects. Do not receive methyltestosterone if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use an effective form of birth control while you are receiving this medication. It is not known whether methyltestosterone passes into breast milk or if it could harm a nursing baby. Do not receive this medication without telling your doctor if you are breast-feeding a baby. Methyltestosterone can affect bone growth in boys who are treated for delayed puberty. Bone development may need to be checked with x-rays every 6 months during treatment.

How should I take Testred (methyltestosterone)?

Take this medication exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results from this medication.

To be sure this medication is helping your condition, your blood will need to be tested on a regular basis. Do not miss any scheduled visits to your doctor.

Methyltestosterone can affect bone growth in boys who are treated for delayed puberty. Bone development may need to be checked with x-rays every 6 months during treatment. Store methyltestosterone at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

An overdose of methyltestosterone is not expected to cause life-threatening symptoms.

What should I avoid while taking Testred (methyltestosterone)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are using methyltestosterone.

Testred (methyltestosterone) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects:

• 
  

  feeling short of breath, even with mild exertion;

  
  


• 
  

  swelling, rapid weight gain;

  
  


• 
  

  increased or ongoing erection of the penis;

  
  


• 
  

  bone pain, increased thirst, memory problems, restless feeling, confusion, nausea, loss of appetite, increased urination, weakness, muscle twitching; or

  
  


• 
  

  nausea, vomiting, stomach pain, loss of appetite, and jaundice (yellowing of the skin or eyes).

  
  

Women receiving methyltestosterone may develop male characteristics, which could be irreversible if testosterone treatment is continued. Stop taking this medication and call your doctor at once if you notice any of these signs of excess testosterone:

• 
  

  changes in menstrual periods;

  
  


• 
  

  male-pattern hair growth (such as on the chin or chest);

  
  


• 
  

  hoarse voice; or

  
  


• enlarged clitoris.

Less serious side effects (in men or women) may include:

• 
  

  acne, changes in skin color;

  
  


• 
  

  breast swelling;

  
  


• 
  

  male pattern baldness;

  
  


• 
  

  headache, anxiety, depressed mood;

  
  


• 
  

  mild nausea;

  
  


• 
  

  numbness or tingly feeling; or

  
  


• 
  

  increased or decreased interest in sex.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Testred (methyltestosterone)?

The following drugs can interact with methyltestosterone. Tell your doctor if you are using any of these:

• 
  

  a blood thinner such as warfarin (Coumadin); or

  
  


• 
  

  insulin or diabetes medication you take by mouth.

  
  

This list is not complete and there may be other drugs that can affect methyltestosterone. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Testred resources

• Testred Side Effects (in more detail)
• Testred Use in Pregnancy & Breastfeeding
• Drug Images
• Testred Drug Interactions
• Testred Support Group
• 0 Reviews for Testred - Add your own review/rating

• Testred MedFacts Consumer Leaflet (Wolters Kluwer)


• Testred Prescribing Information (FDA)


• Android Prescribing Information (FDA)


• Methyltestosterone Professional Patient Advice (Wolters Kluwer)


• Methyltestosterone Monograph (AHFS DI)

Compare Testred with other medications

• Breast Cancer, Palliative
• Delayed Puberty, Male
• Hypogonadism, Male
• Postpartum Breast Pain

Where can I get more information?

• Your pharmacist can provide more information about methyltestosterone.

See also: Testred side effects (in more detail)

Emend 3-Day

Generic Name: aprepitant (a PREP i tant)

Brand Names: Emend, Emend 2-Day, Emend 3-Day

What is Emend 3-Day (aprepitant)?

Aprepitant blocks the actions of chemicals in the body that trigger nausea and vomiting.

Aprepitant is used together with other medications to prevent nausea and vomiting that may be caused by surgery or cancer chemotherapy.

Aprepitant is given ahead of time and will not treat nausea or vomiting that you already have.

Aprepitant may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Emend 3-Day (aprepitant)?

Do not take aprepitant if you are taking any of the following drugs: cisapride (Propulsid) or pimozide (Orap). These drugs may cause life-threatening interactions when taken together with aprepitant. If you have liver disease, you may need an aprepitant dose adjustment or special tests. Aprepitant can make birth control pills less effective, resulting in pregnancy. This effect can last for up to 28 days after your last dose of this medication. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while taking aprepitant and for at least 1 month after your treatment ends.

There are many other drugs that can interact with aprepitant. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

What should I discuss with my health care provider before taking Emend 3-Day (aprepitant)?

You should not use aprepitant if you are allergic to it. These other drugs can cause serious or life-threatening medical problems if you take them together with aprepitant:

• 
  

  cisapride (Propulsid); or

  
  


• 
  

  pimozide (Orap).

  
  

If you have liver disease, you may need an aprepitant dose adjustment or special tests. FDA pregnancy category B. Aprepitant is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether aprepitant passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Emend 3-Day (aprepitant)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Aprepitant can be taken with or without food. If you take aprepitant before surgery, follow your doctor's instructions about any restrictions on food or beverages.

The first dose of aprepitant is usually taken 1 hour before treatment with chemotherapy, or 3 hours before a surgery. You may also need additional doses for a couple days after your chemotherapy treatment. Follow your doctor's instructions.

You may also be given other medicines with aprepitant to further help prevent nausea and vomiting.

Aprepitant is not for long-term use.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Call your doctor for instructions if you forget to take your medicine within the prescribed length of time before your chemotherapy or surgery.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include drowsiness and headache.

What should I avoid while taking Emend 3-Day (aprepitant)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Emend 3-Day (aprepitant) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

• 
  

  feeling like you might pass out;

  
  


• 
  

  feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin; or

  
  


• 
  

  fever, chills, body aches, flu symptoms, sores in your mouth and throat.

  
  

Less serious side effects may include:

• 
  

  nausea, vomiting, heartburn, stomach pain;

  
  


• 
  

  diarrhea or constipation;

  
  


• 
  

  loss of appetite;

  
  


• 
  

  hiccups;

  
  


• 
  

  hair loss;

  
  


• 
  

  headache;

  
  


• 
  

  dizziness;

  
  


• 
  

  tired feeling;

  
  


• 
  

  mild skin rash;

  
  


• 
  

  ringing in your ears; or

  
  


• 
  

  sleep problems (insomnia).

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Emend 3-Day (aprepitant)?

Aprepitant can make birth control pills less effective, resulting in pregnancy. This effect can last for up to 28 days after your last dose of this medication. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while taking aprepitant and for at least 1 month after your treatment ends.

Tell your doctor about all other medicines you use, especially:

• 
  

  tolbutamide (Orinase);

  
  


• 
  

  a blood thinner such as warfarin (Coumadin);

  
  


• 
  

  midazolam (Versed) or similar medicines such as Valium, Xanax, or Tranxene;

  
  


• 
  

  an antidepressant such as nefazodone (Serzone) or paroxetine (Paxil);

  
  


• 
  

  an antibiotic such as clarithromycin (Biaxin) or rifampin (Rifater, Rifamate);

  
  


• 
  

  an antifungal medication such as itraconazole (Sporanox) or ketoconazole (Extina, Ketozole, Nizoral, Xolegal);

  
  


• 
  

  certain cancer medicines such as ifosfamide (Ifex), vinblastine (Velban), or vincristine (Oncovin, Vincasar);

  
  


• 
  

  HIV medicines such as nelfinavir (Viracept), lopinavir/ritonavir (Kaletra), or ritonavir (Norvir);

  
  


• 
  

  seizure medication such as carbamazepine (Tegretol, Carbatrol) or phenytoin (Dilantin); or

  
  


• 
  

  steroid medicine such as dexamethasone (Decadron, Hexadrol) or methylprednisolone (Medapred, Solu-Medrol).

  
  

There are many other drugs that may interact with aprepitant. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

More Emend 3-Day resources

• Emend 3-Day Side Effects (in more detail)
• Emend 3-Day Use in Pregnancy & Breastfeeding
• Emend 3-Day Drug Interactions
• Emend 3-Day Support Group
• 0 Reviews for Emend 3-Day - Add your own review/rating

• Aprepitant Professional Patient Advice (Wolters Kluwer)


• aprepitant Advanced Consumer (Micromedex) - Includes Dosage Information


• Aprepitant MedFacts Consumer Leaflet (Wolters Kluwer)


• Aprepitant/Fosaprepitant Dimeglumine Monograph (AHFS DI)


• Emend Prescribing Information (FDA)


• Emend Consumer Overview

Compare Emend 3-Day with other medications

• Nausea/Vomiting, Chemotherapy Induced
• Nausea/Vomiting, Postoperative

Where can I get more information?

• Your pharmacist can provide more information about aprepitant.

See also: Emend 3-Day side effects (in more detail)

Zyloric Tablets 100mg, 300mg

1. Name Of The Medicinal Product

Zyloric 100 mg Tablets

Zyloric 300 mg Tablets

2. Qualitative And Quantitative Composition

Allopurinol 100 mg (Zyloric Tablets)

Allopurinol 300 mg (Zyloric-300 Tablets)

3. Pharmaceutical Form

Tablet

4. Clinical Particulars

4.1 Therapeutic Indications

Zyloric is indicated for reducing urate/uric acid formation in conditions where urate/uric acid deposition has already occurred (e.g. gouty arthritis, skin tophi, nephrolithiasis) or is a predictable clinical risk (e.g. treatment of malignancy potentially leading to acute uric acid nephropathy). The main clinical conditions where urate/uric acid deposition may occur are: idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate, for example: hypoxanthine-guanine phosphoribosyltransferase, including Lesch-Nyhan syndrome; glucose-6-phosphatase including glycogen storage disease; phosphoribosylpyrophosphate synthetase, phosphoribosylpyrophosphate amidotransferase; adenine phosphoribosyltransferase. Zyloric is indicated for management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of adenine phosphoribosyltransferase.

Zyloric is indicated for the management of recurrent mixed calcium oxalate renal stones in the presence of hyperuricosuria, when fluid, dietary and similar measures have failed.

4.2 Posology And Method Of Administration

Dosage in Adults: Zyloric should be introduced at low dosage e.g. 100mg/day to reduce the risk of adverse reactions and increased only if the serum urate response is unsatisfactory. Extra caution should be exercised if renal function is poor (see Dosage in renal impairment). The following dosage schedules are suggested:

100 to 200 mg daily in mild conditions,

300 to 600 mg daily in moderately severe conditions,

700 to 900 mg daily in severe conditions.

If dosage on a mg/kg bodyweight basis is required, 2 to 10 mg/kg bodyweight/day should be used.

Dosage in children: Children under 15 years: 10 to 20 mg/kg bodyweight/day up to a maximum of 400 mg daily. Use in children is rarely indicated, except in malignant conditions (especially leukaemia) and certain enzyme disorders such as Lesch-Nyhan syndrome.

Dosage in the elderly: In the absence of specific data, the lowest dosage which produces satisfactory urate reduction should be used. Particular attention should be paid to advice in Dosage in renal impairment and Precautions and Warnings.

Dosage in renal impairment: Since allopurinol and its metabolites are excreted by the kidney, impaired renal function may lead to retention of the drug and/or its metabolites with consequent prolongation of plasma half-lives. In severe renal insufficiency, it may be advisable to use less than 100 mg per day or to use single doses of 100mg at longer intervals than one day.

If facilities are available to monitor plasma oxipurinol concentrations, the dose should be adjusted to maintain plasma oxipurinol levels below 100 micromol/litre (15.2 mg/litre).

Allopurinol and its metabolites are removed by renal dialysis. If dialysis is required two to three times a week consideration should be given to an alternative dosage schedule of 300-400 mg Zyloric immediately after each dialysis with none in the interim.

Dosage in hepatic impairment: Reduced doses should be used in patients with hepatic impairment. Periodic liver function tests are recommended during the early stages of therapy.

Treatment of high urate turnover conditions, e.g. neoplasia, Lesch-Nyhan syndrome: It is advisable to correct existing hyperuricaemia and/or hyperuricosuria with Zyloric before starting cytotoxic therapy. It is important to ensure adequate hydration to maintain optimum diuresis and to attempt alkalinisation of urine to increase solubility of urinary urate/uric acid. Dosage of Zyloric should be at the lower end of the recommended dosage schedule.

If urate nephropathy or other pathology has compromised renal function, the advice given in Dosage in renal impairment should be followed.

These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the clinical situation. See also Drug Interactions And Adverse Reactions.

Monitoring Advice: The dosage should be adjusted by monitoring serum urate concentrations and urinary urate/uric acid levels at appropriate intervals.

Instructions for Use: Zyloric may be taken orally once a day after a meal. It is well tolerated, especially after food. Should the daily dosage exceed 300 mg and gastrointestinal intolerance be manifested, a divided doses regimen may be appropriate.

4.3 Contraindications

Zyloric should not be administered to individuals known to be hypersensitive to allopurinol or to any of the components of the formulation.

4.4 Special Warnings And Precautions For Use

Zyloric should be withdrawn immediately when a skin rash or other evidence of sensitivity occurs as this could result in more serious hypersensitivity reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) (see Adverse Reactions – Immune system disorders and Skin and subcutaneous tissue disorders).

Reduced doses should be used in patients with hepatic or renal impairment. Patients under treatment for hypertension or cardiac insufficiency, for example with diuretics or ACE inhibitors, may have some concomitant impairment of renal function and allopurinol should be used with care in this group.

Asymptomatic hyperuricaemia per se is generally not considered an indication for use of Zyloric. Fluid and dietary modification with management of the underlying cause may correct the condition.

Acute gouty attacks: Allopurinol treatment should not be started until an acute attack of gout has completely subsided, as further attacks may be precipitated.

In the early stages of treatment with Zyloric, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. Therefore it is advisable to give prophylaxis with a suitable anti-inflammatory agent or colchicine for at least one month. The literature should be consulted for details of appropriate dosage and precautions and warnings.

If acute attacks develop in patients receiving allopurinol, treatment should continue at the same dosage while the acute attack is treated with a suitable anti-inflammatory agent.

Xanthine deposition: In conditions where the rate of urate formation is greatly increased (e.g. malignant disease and its treatment, Lesch-Nyhan syndrome) the absolute concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. This risk may be minimised by adequate hydration to achieve optimal urine dilution.

Impaction of uric acid renal stones: Adequate therapy with Zyloric will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.

Lactose intolerance: Zyloric tablets contain lactose and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

6 -mercaptopurine and azathioprine: Azathioprine is metabolised to 6-mercaptopurine which is inactivated by the action of xanthine oxidase. When 6-mercaptopurine or azathioprine is given concurrently with Zyloric, only one-quarter of the usual dose of 6-mercaptopurine or azathioprine should be given because inhibition of xanthine oxidase will prolong their activity.

Vidarabine (Adenine Arabinoside): Evidence suggests that the plasma half-life of vidarabine is increased in the presence of allopurinol. When the two products are used concomitantly extra vigilance is necessary, to recognise enhanced toxic effects.

Salicylates and uricosuric agents: oxipurinol, the major metabolite of allopurinol and itself therapeutically active, is excreted by the kidney in a similar way to urate. Hence, drugs with uricosuric activity such as probenecid or large doses of salicylate may accelerate the excretion of oxipurinol. This may decrease the therapeutic activity of Zyloric, but the significance needs to be assessed in each case.

Chlorpropamide: If Zyloric is given concomitantly with chlorpropamide when renal function is poor, there may be an increased risk of prolonged hypoglycaemic activity because allopurinol and chlorpropamide may compete for excretion in the renal tubule.

Coumarin anticoagulants

There have been rare reports of increased effect of warfarin and other coumarin anticoagulants when co-administered with allopurinol, therefore, all patients receiving anticoagulants must be carefully monitored.

Phenytoin: Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.

Theophylline: Inhibition of the metabolism of theophylline has been reported. The mechanism of the interaction may be explained by xanthine oxidase being involved in the biotransformation of theophylline in man. Theophylline levels should be monitored in patients starting or increasing allopurinol therapy.

Ampicillin/Amoxicillin: An increase in frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs. The cause of the reported association has not been established. However, it is recommended that in patients receiving allopurinol an alternative to ampicillin or amoxicillin is used where available.

Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechloroethamine: Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease (other than leukaemia), in the presence of allopurinol. However, in a well-controlled study of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechloroethamine (chlormethine hydrochloride) allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.

Ciclosporin: Reports suggest that the plasma concentration of ciclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin toxicity should be considered if the drugs are co-administered.

Didanosine: In healthy volunteers and HIV patients receiving didanosine, plasma didanosine C_max and AUC values were approximately doubled with concomitant allopurinol treatment (300 mg daily) without affecting terminal half life. Co-administration of these 2 drugs is generally not recommended. If concomitant use is unavoidable, a dose reduction of didanosine may be required, and patients should be closely monitored.

4.6 Pregnancy And Lactation

There is inadequate evidence of safety of Zyloric in human pregnancy, although it has been in wide use for many years without apparent ill consequence.

Use in pregnancy only when there is no safer alternative and when the disease itself carries risk for the mother or unborn child.

Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of 1.4mg/litre allopurinol and 53.7 mg/litre oxipurinol have been demonstrated in breast milk from woman taking Zyloric 300 mg/day. However, there are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.

4.7 Effects On Ability To Drive And Use Machines

Since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients receiving allopurinol, patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that allopurinol does not adversely affect performance.

4.8 Undesirable Effects

For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.

The frequency categories assigned to the adverse drug reactions below are estimates: for most reactions, suitable data for calculating incidence are not available. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare. The following convention has been used for the classification of frequency:

Very common
Common
Uncommon
Rare
Very rare	<1/10,000 (<0.01%)

Adverse reactions in association with Zyloric are rare in the overall treated population and mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic disorder.

Infections and infestations

Very rare

Furunculosis

Blood and lymphatic system disorders

Very rare

Agranulocytosis, aplastic anaemia, thrombocytopenia

Very rare reports have been received of thrombocytopenia, agranulocytosis and aplastic anaemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing the need for particular care in this group of patients.

Immune system disorders

Uncommon	Hypersensitivity reactions
Very rare	Angioimmunoblastic lymphadenopathy

Serious hypersensitivity reactions, including skin reactions associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis occur rarely (see Skin and subcutaneous tissue disorders). Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment and very rarely, seizures. Very rarely acute anaphylactic shock has been reported. If such reactions do occur, it may be at any time during treatment, Zyloric should be withdrawn immediately and permanently.

Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions. When generalised hypersensitivity reactions have occurred, renal and/or hepatic disorder has usually been present particularly when the outcome has been fatal.

Angioimmunoblastic lymphadenopathy has been described very rarely following biopsy of a generalised lymphadenopathy. It appears to be reversible on withdrawal of Zyloric.

Metabolism and nutrition disorders

Very rare

Diabetes mellitus, hyperlipidaemia

Psychiatric disorders

Very rare

Depression

Nervous system disorders

Very rare

Coma, paralysis, ataxia, neuropathy, paraesthesiae, somnolence, headache, taste perversion

Eye disorders

Very rare

Cataract, visual disorder, macular changes

Ear and labyrinth disorders

Very rare

Vertigo

Cardiac disorders

Very rare

Angina, bradycardia

Vascular disorders

Very rare

Hypertension

Gastrointestinal disorders

Uncommon	Vomiting, nausea
Very rare	Recurrent haematemesis, steatorrhoea, stomatitis, changed bowel habit

In early clinical studies, nausea and vomiting were reported. Further reports suggest that this reaction is not a significant problem and can be avoided by taking Zyloric after meals.

Hepatobiliary disorders

Uncommon	Asymptomatic increases in liver function tests
Rare	Hepatitis (including hepatic necrosis and granulomatous hepatitis)

Hepatic dysfunction has been reported without overt evidence of more generalised hypersensitivity.

Skin and subcutaneous tissue disorders

Common	Rash
Rare	Stevens-Johnson syndrome/toxic epidermal necrolysis
Very rare	Angioedema, fixed drug eruption, alopecia, discoloured hair

Skin reactions are the most common reactions and may occur at any time during treatment. They may be pruritic, maculopapular, sometimes scaly, sometimes purpuric and rarely exfoliative, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN).

Zyloric should be withdrawn immediately should such reactions occur. After recovery from mild reactions, Zyloric may, if desired, be re-introduced at a small dose (e.g. 50mg/day) and gradually increased. If the rash recurs, Zyloric should be permanently withdrawn as more severe hypersensitivity may occur (see Immune system disorders).

The HLA-B*5801 allele has been has been identified as a genetic risk factor for allopurinol associated SJS/TEN in retrospective, case-control, pharmacogenetic studies in patients of Han Chinese, Japanese and European descent. Up to 20-30% of some Han Chinese, African and Indian populations carry the HLA-B*5801 allele whereas only 1-2% of Northern European, US European and Japanese patients are estimated to be HLA-B*5801 carriers. However, the use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established.

The clinical diagnosis of SJS/TEN remains the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately and permanently.

Angioedema has been reported to occur with and without signs and symptoms of a more generalised hypersensitivity reaction.

Renal and urinary disorders

Very rare

Haematuria, uraemia

Reproductive system and breast disorders

Very rare

Male infertility, erectile dysfunction, gynaecomastia

General disorders and administration site conditions

Very rare

Oedema, general malaise, asthenia, fever

Fever has been reported to occur with and without signs and symptoms of a more generalised Zyloric hypersensitivity reaction (see Immune system disorders).

4.9 Overdose

Ingestion of up to 22.5 g allopurinol without adverse effect has been reported. Symptoms and signs including nausea, vomiting, diarrhoea and dizziness have been reported in a patient who ingested 20 g allopurinol. Recovery followed general supportive measures. Massive absorption of Zyloric may lead to considerable inhibition of xanthine oxidase activity, which should have no untoward effects unless affecting concomitant medication, especially with 6-mercaptopurine and/or azathioprine. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. If considered necessary haemodialysis may be used.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Allopurinol is a xanthine-oxidase inhibitor. Allopurinol and its main metabolite oxipurinol lower the level of uric acid in plasma and urine by inhibition of xanthine oxidase, the enzyme catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In addition to the inhibition of purine catabolism in some but not all hyperuricaemic patients, de novo purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine phosphoribosyltransferase. Other metabolites of allopurinol include allopurinol-riboside and oxipurinol-7 riboside.

5.2 Pharmacokinetic Properties

Allopurinol is active when given orally and is rapidly absorbed from the upper gastrointestinal tract. Studies have detected allopurinol in the blood 30-60 minutes after dosing. Estimates of bioavailability vary from 67% to 90%. Peak plasma levels of allopurinol generally occur approximately 1.5 hours after oral administration of Zyloric, but fall rapidly and are barely detectable after 6 hours. Peak levels of oxipurinol generally occur after 3-5 hours after oral administration of Zyloric and are much more sustained.

Allopurinol is negligibly bound by plasma proteins and therefore variations in protein binding are not thought to significantly alter clearance. The apparent volume of distribution of allopurinol is approximately 1.6 litre/kg which suggests relatively extensive uptake by tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is likely that allopurinol and oxipurinol will be present in the highest concentrations in the liver and intestinal mucosa where xanthine oxidase activity is high.

Approximately 20% of the ingested allopurinol is excreted in the faeces. Elimination of allopurinol is mainly by metabolic conversion to oxipurinol by xanthine oxidase and aldehyde oxidase, with less than 10% of the unchanged drug excreted in the urine. Allopurinol has a plasma half-life of about 1 to 2 hours.

Oxipurinol is a less potent inhibitor of xanthine oxidase than allopurinol, but the plasma half-life of oxipurinol is far more prolonged. Estimates range from 13 to 30 hours in man. Therefore effective inhibition of xanthine oxidase is maintained over a 24 hour period with a single daily dose of Zyloric. Patients with normal renal function will gradually accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such patients, taking 300 mg of allopurinol per day will generally have plasma oxipurinol concentrations of 5-10 mg/litre.

Oxipurinol is eliminated unchanged in the urine but has a long elimination half-life because it undergoes tubular reabsorption. Reported values for the elimination half-life range from 13.6 hours to 29 hours. The large discrepancies in these values may be accounted for by variations in study design and/or creatinine clearance in the patients.

Pharmacokinetics in patients with renal impairment.

Allopurinol and oxipurinol clearance is greatly reduced in patients with poor renal function resulting in higher plasma levels in chronic therapy. Patients with renal impairment, where creatinine clearance values were between 10 and 20ml/min, showed plasma oxipurinol concentrations of approximately 30mg/litre after prolonged treatment with 300 mg allopurinol per day. This is approximately the concentration which would be achieved by doses of 600 mg/day in those with normal renal function. A reduction in the dose of Zyloric is therefore required in patients with renal impairment.

Pharmacokinetics in elderly patients.

The kinetics of the drug are not likely to be altered other than due to deterioration in renal function (see Pharmocokinetics in patients with renal impairment).

5.3 Preclinical Safety Data

A. Mutagenicity

Cytogenetic studies show that allopurinol does not induce chromosome aberrations in human blood cells in vitro at concentrations up to 100 micrograms/ml and in vivo at doses up to 600 mg/day for mean period of 40 months.

Allopurinol does not produce nitraso compounds in vitro or affect lymphocyte transformation in vitro.

Evidence from biochemical and other cytological investigations strongly suggests that allopurinol has no deleterious effects on DNA at any stage of the cell cycle and is not mutagenic.

B. Carcinogenicity

No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for up to 2 years.

C. Teratogenicity

One study in mice receiving intraperitoneal doses of 50 or 100 mg/kg on days 10 or 13 of gestation resulted in foetal abnormalities, however in a similar study in rats at 120 mg/kg on day 12 of gestation no abnormalities were observed. Extensive studies of high oral doses of allopurinol in mice up to 100 mg/kg/day, rats up to 200 mg/kg/day and rabbits up to 150 mg/kg/day during days 8 to 16 of gestation produced no teratogenic effects.

An in vitro study using foetal mouse salivary glands in culture to detect embryotoxicity indicated that allopurinol would not be expected to cause embryotoxicity without also causing maternal toxicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Maize Starch

Povidone

Magnesium Stearate

Purified Water

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package

6.5 Nature And Contents Of Container

Zyloric 100mg Tablets

PVC/aluminium foil blister pack

Zyloric-300 Tablets

PVC/aluminium foil blister pack

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

Administrative Data

7. Marketing Authorisation Holder

Aspen Europe GmbH,

Industriestrasse 32-36,

D-23843 Bad Oldesloe,

Germany

8. Marketing Authorisation Number(S)

PL 00003/5207R – Zyloric 100mg Tablets

PL 00003/0092R – Zyloric-300 Tablets

9. Date Of First Authorisation/Renewal Of The Authorisation

Zyloric 100mg Tablets	Zyloric-300 Tablets
MAA: 20.03.80	14.07.80
Renewal: 06.06.90	18.02.91
Renewal: 14.11.95	25.11.98

10. Date Of Revision Of The Text

13 October 2009

11. Legal Status

POM

Isoniazida Fabra

Isoniazida Fabra may be available in the countries listed below.

Ingredient matches for Isoniazida Fabra

Isoniazid

Isoniazid is reported as an ingredient of Isoniazida Fabra in the following countries:

• Argentina

International Drug Name Search

Sulfatol Cleanser

Dosage Form: topical solution
Sulfatol™ Cleanser (Sodium Sulfacetamide 10%, and Sulfur 5% in a Urea Vehicle)

Rx Only

Sulfatol Cleanser Description

Sodium Sulfacetamide is a sulfonamide with antibacterial activity. Sulfur acts as a keratolytic agent. Chemically, sodium sulfacetamide is N-[(4-aminophenyl) sulfonyl]-acetamide, monosodium salt, monohydrate. The structural formula is:

Each mL of Sulfatol™ Cleanser (Sodium Sulfacetamide 10%, and Sulfur 5% in a Urea vehicle) contains 100 mg of Sodium Sulfacetamide and 50 mg of Sulfur in an emulsion base containing Urea 10%, BHT, Cetyl Alcohol, Disodium EDTA, Fragrance, Disodium Oleamido MEA Sulfosuccinate, Glyceryl and PEG-100 Stearate, Magnesium Aluminum Silicate, Methylparaben, Propylparaben, Sodium Cocoyl Isethionate, Sodium Methyl Cocoyl Taurate, Sodium Thiosulfate, Stearyl Alcohol, Purified Water, Xanthan Gum.

Sulfatol Cleanser - Clinical Pharmacology

The most widely accepted mechanism of action of sulfonamides is the Woods-Fildes theory, which is based on the fact that sulfonamides act as competitive antagonists to para-aminobenzoic acid (PABA), an essential component for bacterial growth. While absorption through intact skin has not been determined, sodium sulfacetamide is readily absorbed from the gastrointestinal tract when taken orally and excreted in the urine, largely unchanged. The biological half-life has variously been reported as 7 to 12.8 hours. The exact mode of action of sulfur in the treatment of acne is unknown, but it has been reported that it inhibits the growth of Propionibacterium acnes and the formation of free fatty acids.

INDICATIONS

Sulfatol™ Cleanser is indicated in the topical control of acne vulgaris, acne rosacea and seborrheic dermatitis.

Contraindications

Sulfatol™ Cleanser is contraindicated for use by patients having known hypersensitivity to sulfonamides, sulfur or any other component of this preparation. Sulfatol™ Cleanser is not to be used by patients with kidney disease.

Warnings

Although rare, sensitivity to sodium sulfacetamide may occur. Therefore, caution and careful supervision should be observed when prescribing this drug for patients who may be prone to hypersensitivity to topical sulfonamides. Systemic toxic reactions such as agranulocytosis, acute hemolytic anemia, purpura hemorrhagica, drug fever, jaundice, and contact dermatitis indicate hypersensitivity to sulfonamides. Particular caution should be employed if areas of denuded or abraded skin are involved.

FOR EXTERNAL USE ONLY. Keep away from eyes. Keep out of reach of children. Keep bottle tightly closed.

Precautions

General

If irritation develops, use of the product should be discontinued and appropriate therapy instituted. Patients should be carefully observed for possible local irritation or sensitization during long-term therapy. The object of this therapy is to achieve desquamation without irritation, but sodium sulfacetamide and sulfur can cause reddening and scaling of the epidermis. These side effects are not unusual in the treatment of acne vulgaris but patients should be cautioned about the possibility.

Information for Patients

Avoid contact with eyes, eyelids, lips and mucous membranes. If accidental contact occurs rinse with water. If excessive irritation develops, discontinue use and consult your physician.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Pregnancy

Category C

Animal reproduction studies have not been conducted with Sulfatol™ Cleanser. It also is not known whether Sulfatol™ Cleanser can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sulfatol™ Cleanser should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether sodium sulfacetamide is excreted in human milk following topical use of Sulfatol™ Cleanser. However, small amounts of orally administered sulfonamides have been reported to be eliminated in human milk. In view of this and because many drugs are excreted in human milk, caution should be exercised when Sulfatol™ Cleanser is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children under the age of 12 have not been established.

Adverse Reactions

Although rare, sodium sulfacetamide may cause local irritation.

Sulfatol Cleanser Dosage and Administration

Sulfatol™ Cleanser

Wash affected area once or twice daily or as directed by your physician. Avoid contact with eyes or mucous membranes. Wet skin and liberally apply to areas to be cleansed, massage gently into skin for 10-20 seconds, working into a full lather, rinse thoroughly and pat dry. If drying occurs, it may be controlled by rinsing off cleanser sooner or using less often.

How is Sulfatol Cleanser Supplied

Sulfatol™ Cleanser is available in a 355 mL bottle. NDC 51991-173-26

Storage

Store at 25° C (77° F); excursions permitted to 15°-30° C (59°-86° F). See USP Controlled Room Temperature.

Protect from freezing.

Distributed by: Breckenridge Pharmaceutical, Inc., Boca Raton, FL 33487

Manufactured by: Groupe Parima Inc., Montréal, QC Canada H4S 1X6

06/07

PRINCIPAL DISPLAY PANEL - 355 mL Bottle Carton

Breckenridge

Pharmaceutical, Inc.

NDC 51991-173-26

Sulfatol™ Cleanser

Sodium Sulfacetamide 10%, Sulfur 5% in a Urea vehicle

Skin Cleanser

For The Topical Treatment Of

• Acne Vulgaris


• Acne Rosacea


• Seborrheic Dermatitis

Rx ONLY

Net Wt. 355 mL

Sulfatol Cleanser  sulfacetamide sodium and sulfur  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 51991-173 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sulfacetamide Sodium (Sulfacetamide) Sulfacetamide Sodium 100 mg  in 1 mL Sulfur (Sulfur) Sulfur 50 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength Butylated Hydroxytoluene   Cetyl Alcohol   Edetate Disodium   Glyceryl Monostearate   Disodium Oleamido MEA-Sulfosuccinate   Polyoxyl 100 Stearate   Magnesium Aluminum Silicate   Methylparaben   Propylparaben   Sodium Cocoyl Isethionate   Sodium Thiosulfate   Stearyl Alcohol   Urea   Water   Xanthan Gum

Product Characteristics Color YELLOW (light-yellow) Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 51991-173-26 1 BOTTLE In 1 BOX contains a BOTTLE 1 355 mL In 1 BOTTLE This package is contained within the BOX (51991-173-26)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
UNAPPROVED DRUG OTHER		03/01/2005	09/30/2011

Labeler - Breckenridge Pharmaceutical, Inc. (150554335)

Establishment
Name	Address	ID/FEI	Operations
Groupe Parima		252437850	MANUFACTURE

Revised: 11/2010Breckenridge Pharmaceutical, Inc.

More Sulfatol Cleanser resources

• Sulfatol Cleanser Side Effects (in more detail)
• Sulfatol Cleanser Use in Pregnancy & Breastfeeding
• Sulfatol Cleanser Drug Interactions
• Sulfatol Cleanser Support Group
• 18 Reviews for Sulfatol - Add your own review/rating

• Sulfatol Cleanser Emulsion MedFacts Consumer Leaflet (Wolters Kluwer)


• Rosula CLK Kit MedFacts Consumer Leaflet (Wolters Kluwer)


• Sulfatol Gel MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Sulfatol Cleanser with other medications

• Acne
• Rosacea
• Seborrheic Dermatitis