Timoptic

timolol maleate

Dosage Form: ophthalmic solution
Timoptic®

0.25% AND 0.5%

(TIMOLOL MALEATE OPHTHALMIC SOLUTION)

in OCUDOSE® (DISPENSER)

PRESERVATIVE-FREE STERILE OPHTHALMIC SOLUTION in a Sterile Ophthalmic Unit Dose Dispenser

Timoptic Description

Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. Its chemical name is (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. The optical rotation of timolol maleate is:

[α]

25° 405 nm

in 1.0N HCl (C = 5%) = –12.2° (–11.7° to –12.5°).

Its molecular formula is C13H24N4O3S•C4H4O4 and its structural formula is:

Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol. Timolol maleate is stable at room temperature.

Timolol maleate ophthalmic solution is supplied in two formulations: Ophthalmic Solution Timoptic1 (timolol maleate ophthalmic solution), which contains the preservative benzalkonium chloride; and Ophthalmic Solution Timoptic1 (timolol maleate ophthalmic solution), the preservative-free formulation.

Preservative-free Ophthalmic Solution Timoptic is supplied in OCUDOSE1, a unit dose container, as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths: Each mL of Preservative-free Timoptic in OCUDOSE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). The pH of the solution is approximately 7.0, and the osmolarity is 252-328 mOsm. Each mL of Preservative-free Timoptic in OCUDOSE 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: monobasic and dibasic sodium phosphate, sodium hydroxide to adjust pH, and water for injection.

1

Registered trademark of ATON PHARMA, INC.

COPYRIGHT © 2009 ATON PHARMA, INC.

All rights reserved

Timoptic - Clinical Pharmacology

Mechanism of Action

Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity.

Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor blockade may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function.

Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from unopposed parasympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.

Timoptic (timolol maleate ophthalmic solution), when applied topically on the eye, has the action of reducing elevated as well as normal intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage.

The onset of reduction in intraocular pressure following administration of Timoptic (timolol maleate ophthalmic solution) can usually be detected within one-half hour after a single dose. The maximum effect usually occurs in one to two hours and significant lowering of intraocular pressure can be maintained for periods as long as 24 hours with a single dose. Repeated observations over a period of one year indicate that the intraocular pressure-lowering effect of Timoptic (timolol maleate ophthalmic solution) is well maintained.

The precise mechanism of the ocular hypotensive action of Timoptic (timolol maleate ophthalmic solution) is not clearly established at this time. Tonography and fluorophotometry studies in man suggest that its predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed.

Pharmacokinetics

In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following twice daily administration of Timoptic 0.5%. The mean peak plasma concentration following morning dosing was 0.46 ng/mL and following afternoon dosing was 0.35 ng/mL.

Clinical Studies

In controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmHg or greater, Timoptic (timolol maleate ophthalmic solution) 0.25 percent or 0.5 percent administered twice a day produced a greater reduction in intraocular pressure than 1, 2, 3, or 4 percent pilocarpine solution administered four times a day or 0.5, 1, or 2 percent epinephrine hydrochloride solution administered twice a day.

In these studies, Timoptic (timolol maleate ophthalmic solution) was generally well tolerated and produced fewer and less severe side effects than either pilocarpine or epinephrine. A slight reduction of resting heart rate in some patients receiving Timoptic (timolol maleate ophthalmic solution) (mean reduction 2.9 beats/minute standard deviation 10.2) was observed.

Indications and Usage for Timoptic

Preservative-free Timoptic in OCUDOSE is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Preservative-free Timoptic in OCUDOSE may be used when a patient is sensitive to the preservative in Timoptic (timolol maleate ophthalmic solution), benzalkonium chloride, or when use of a preservative-free topical medication is advisable.

Contraindications

Preservative-free Timoptic in OCUDOSE is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease (see WARNINGS); (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure (see WARNINGS); (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.

Warnings

As with many topically applied ophthalmic drugs, this drug is absorbed systemically.

The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate (see CONTRAINDICATIONS).

Cardiac Failure

Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.

In Patients Without a History of Cardiac Failure continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, Preservative-free Timoptic in OCUDOSE should be discontinued.

Obstructive Pulmonary Disease

Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which Timoptic in OCUDOSE is contraindicated [see CONTRAINDICATIONS]) should, in general, not receive beta-blockers, including Preservative-free Timoptic in OCUDOSE.

Major Surgery

The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have experienced protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents.

If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.

Diabetes Mellitus

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis

Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.

Precautions

General

Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Preservative-free Timoptic in OCUDOSE, alternative therapy should be considered.

Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g. timolol).

Angle-closure glaucoma

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil. Timolol maleate has little or no effect on the pupil. Timoptic in OCUDOSE should not be used alone in the treatment of angle-closure glaucoma.

Anaphylaxis

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

Information for Patients

Patients should be instructed about the use of Preservative-free Timoptic in OCUDOSE.

Since sterility cannot be maintained after the individual unit is opened, patients should be instructed to use the product immediately after opening, and to discard the individual unit and any remaining contents immediately after use.

Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take this product. (See CONTRAINDICATIONS.)

Drug Interactions

Although Timoptic (timolol maleate ophthalmic solution) used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with Timoptic (timolol maleate ophthalmic solution) and epinephrine has been reported occasionally.

Beta-adrenergic blocking agents

Patients who are receiving a beta-adrenergic blocking agent orally and Preservative-free Timoptic in OCUDOSE should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.

Calcium antagonists

Caution should be used in the coadministration of beta-adrenergic blocking agents, such as Preservative-free Timoptic in OCUDOSE, and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, coadministration should be avoided.

Catecholamine-depleting drugs

Close observation of the patient is recommended when a beta blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension.

Digitalis and calcium antagonists

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

CYP2D6 inhibitors

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol.

Clonidine

Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate.

Injectable epinephrine

(See PRECAUTIONS, General, Anaphylaxis)

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year oral study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose.

In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000 times, respectively, the systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.

The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.

Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.

Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Teratogenicity studies with timolol in mice, rats and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.

There are no adequate and well-controlled studies in pregnant women. Preservative-free Timoptic in OCUDOSE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Adverse Reactions

The most frequently reported adverse experiences have been burning and stinging upon instillation (approximately one in eight patients).

The following additional adverse experiences have been reported less frequently with ocular administration of this or other timolol maleate formulations:

BODY AS A WHOLE

Headache, asthenia/fatigue, and chest pain.

CARDIOVASCULAR

Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, edema, claudication, Raynaud's phenomenon, and cold hands and feet.

DIGESTIVE

Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.

IMMUNOLOGIC

Systemic lupus erythematosus.

NERVOUS SYSTEM/PSYCHIATRIC

Dizziness, increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia, nightmares, behavioral changes and psychic disturbances including depression, confusion, hallucinations, anxiety, disorientation, nervousness, and memory loss.

SKIN

Alopecia and psoriasiform rash or exacerbation of psoriasis.

HYPERSENSITIVITY

Signs and symptoms of systemic allergic reactions including anaphylaxis, angioedema, urticaria, and localized and generalized rash.

RESPIRATORY

Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough and upper respiratory infections.

ENDOCRINE

Masked symptoms of hypoglycemia in diabetic patients (see WARNINGS).

SPECIAL SENSES

Signs and symptoms of ocular irritation including conjunctivitis, blepharitis, keratitis, ocular pain, discharge (e.g., crusting), foreign body sensation, itching and tearing, and dry eyes; ptosis; decreased corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia; pseudopemphigoid; choroidal detachment following filtration surgery (see PRECAUTIONS, General); and tinnitus.

UROGENITAL

Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease.

The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate or other ORAL beta blocking agents, and may be considered potential effects of ophthalmic timolol maleate: Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular: Worsening of arterial insufficiency, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly, vomiting, mesenteric arterial thrombosis, ischemic colitis; Hematologic: Nonthrombocytopenic purpura; thrombocytopenic purpura; agranulocytosis; Endocrine: Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: Vertigo, local weakness, diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination difficulties.

Overdosage

There have been reports of inadvertent overdosage with Ophthalmic Solution Timoptic (timolol maleate ophthalmic solution) resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see also ADVERSE REACTIONS).

Overdosage has been reported with Tablets BLOCADREN1 (timolol maleate tablets). A 30 year old female ingested 650 mg of BLOCADREN (maximum recommended oral daily dose is 60 mg) and experienced second and third degree heart block. She recovered without treatment but approximately two months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree heart block.

An in vitro hemodialysis study, using 14C timolol added to human plasma or whole blood, showed that timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not dialyze readily.

Timoptic Dosage and Administration

Preservative-free Timoptic in OCUDOSE is a sterile solution that does not contain a preservative. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be guaranteed after the individual unit is opened, the remaining contents should be discarded immediately after administration.

Preservative-free Timoptic in OCUDOSE is available in concentrations of 0.25 and 0.5 percent. The usual starting dose is one drop of 0.25 percent Preservative-free Timoptic in OCUDOSE in the affected eye(s) administered twice a day. Apply enough gentle pressure on the individual container to obtain a single drop of solution. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected eye(s) administered twice a day.

Since in some patients the pressure-lowering response to Preservative-free Timoptic in OCUDOSE may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Preservative-free Timoptic in OCUDOSE.

If the intraocular pressure is maintained at satisfactory levels, the dosage schedule may be changed to one drop once a day in the affected eye(s). Because of diurnal variations in intraocular pressure, satisfactory response to the once-a-day dose is best determined by measuring the intraocular pressure at different times during the day.

Dosages above one drop of 0.5 percent Timoptic (timolol maleate ophthalmic solution) twice a day generally have not been shown to produce further reduction in intraocular pressure. If the patient's intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy with other agent(s) for lowering intraocular pressure can be instituted taking into consideration that the preparation(s) used concomitantly may contain one or more preservatives. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. (See PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents.)

How is Timoptic Supplied

Preservative-free Sterile Ophthalmic Solution Timoptic in OCUDOSE is a clear, colorless to light yellow solution.

No. 814– Preservative-free Timoptic, 0.25% timolol equivalent, is supplied in OCUDOSE, a clear low density polyethylene unit dose container. Each individual unit contains 0.2 mL of solution, and is available in a foil laminate overwrapped pouch as follows:

NDC 25010-814-66; 60 Individual Unit Doses.

No. 815– Preservative-free Timoptic, 0.5% timolol equivalent, is supplied in OCUDOSE, a clear low density polyethylene unit dose container. Each individual unit contains 0.2 mL of solution, and is available in a foil laminate overwrapped pouch as follows:

NDC 25010-815-66; 60 Individual Unit Doses.

Storage

Store at room temperature, 15-30°C (59-86°F). Protect from freezing. Protect from light.

Because evaporation can occur through the unprotected polyethylene unit dose container and prolonged exposure to direct light can modify the product, the unit dose container should be kept in the protective foil overwrap and used within one month after the foil package has been opened.

Manuf. for:

ATON PHARMA

Lawrenceville

NJ 08648

USA

By: Laboratories Merck Sharp & Dohme-Chibret

63963 Clermont-Ferrand Cedex 9, France

Issued February 2009

PRINCIPAL DISPLAY PANEL - 0.25% Carton

Rx only

NDC 25010-814-66

Timoptic® in OCUDOSE®

(TIMOLOL MALEATE

OPHTHALMIC SOLUTION)

(DISPENSER)

0.25%

Timolol Equivalent (Timolol Maleate 3.4 mg/mL)

60 x 0.2 mL UNIT DOSES

FOR TOPICAL APPLICATION IN THE EYE

PRESERVATIVE-FREE STERILE

OPHTHALMIC SOLUTION

ATON

PHARMA

Manufactured for:

ATON PHARMA, INC., Lawrenceville, NJ 08648, USA

By: Laboratories Merck Sharp & Dohme-Chibret

63963 Clermont-Ferrand Cedex 9, France

Made in France

PRINCIPAL DISPLAY PANEL - 0.5% Carton

Rx only

NDC 25010-815-66

Timoptic® in OCUDOSE®

(TIMOLOL MALEATE

OPHTHALMIC SOLUTION)

(DISPENSER)

0.5%

Timolol Equivalent (Timolol Maleate 6.8 mg/mL)

60 x 0.2 mL UNIT DOSES

FOR TOPICAL APPLICATION IN THE EYE

PRESERVATIVE-FREE STERILE

OPHTHALMIC SOLUTION

ATON

PHARMA

Manufactured for:

ATON PHARMA, INC., Lawrenceville, NJ 08648, USA

By: Laboratories Merck Sharp & Dohme-Chibret

63963 Clermont-Ferrand Cedex 9, France

Made in France

Timoptic  timolol maleate  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 25010-814 Route of Administration OPHTHALMIC DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Timolol Maleate (Timolol) Timolol 2.5 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength Sodium Phosphate, Monobasic   Sodium Phosphate, Dibasic   Sodium Hydroxide   Water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 25010-814-66 4 POUCH In 1 CARTON contains a POUCH 1 15 CONTAINER In 1 POUCH This package is contained within the CARTON (25010-814-66) and contains a CONTAINER 1 0.2 mL In 1 CONTAINER This package is contained within a POUCH and a CARTON (25010-814-66)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019463	11/05/1986

Timoptic  timolol maleate  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 25010-815 Route of Administration OPHTHALMIC DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Timolol Maleate (Timolol) Timolol 5.0 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength Sodium Phosphate, Monobasic   Sodium Phosphate, Dibasic   Sodium Hydroxide   Water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 25010-815-66 4 POUCH In 1 CARTON contains a POUCH 1 15 CONTAINER In 1 POUCH This package is contained within the CARTON (25010-815-66) and contains a CONTAINER 1 0.2 mL In 1 CONTAINER This package is contained within a POUCH and a CARTON (25010-815-66)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019463	11/05/1986

Labeler - Aton Pharma, Inc. (795419675)

Establishment
Name	Address	ID/FEI	Operations
Laboratories Merck Sharp & Dohme - Chibret		493743686	MANUFACTURE

Revised: 10/2011Aton Pharma, Inc.

More Timoptic resources

• Timoptic Side Effects (in more detail)
• Timoptic Dosage
• Timoptic Use in Pregnancy & Breastfeeding
• Timoptic Drug Interactions
• Timoptic Support Group
• 1 Review for Timoptic - Add your own review/rating

Compare Timoptic with other medications

• Glaucoma, Open Angle
• Intraocular Hypertension

Minocycline Tablets 50mg, 100mg (Actavis UK Ltd)

Minocycline 50mg and 100mg tablets

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them,
  even if their symptoms are the same as yours.

Index

• 1 What Minocycline tablets are and what they are used for


• 2 Before you take


• 3 How to take


• 4 Possible side effects


• 5 How to store


• 6 Further information

What Minocycline tablets are and what they are used for

Minocycline belongs to a group of medicines called tetracycline antibiotics. It is also known as a broad-spectrum antibiotic and may be used to treat a wide range of infections caused by bacteria. Minocycline may be used for:

• respiratory tract infections such as pneumonia, bronchiectasis, lung abscess or bronchitis


• urinary tract infections


• gonorrhoea (a sexually transmitted disease)


• skin infections such as acne


• infections of the eye


• prostate infections


• ear, nose and throat infections


• nocardiosis (an infection often affecting the lungs)


• pelvic inflammatory disease (e.g. salpingitis, oophoritis)


• preventative treatment for meningitis carriers


• preventative treatment before and after surgery.

Before you take

Do not take Minocycline tablets and tell your doctor if you:

• are allergic (hypersensitive) to minocycline hydrochloride, other similar antibiotics (such as tetracycline or doxycycline) or any other ingredient in Minocycline tablets (see section 6)



• have had complete kidney failure



• are pregnant or breast-feeding



• are giving it to a child under 12 years old.

Take special care with Minocycline tablets and tell your doctor if you:

• suffer from myasthenia gravis, a condition characterised by muscle weakness, difficulty chewing and swallowing and slurred speech



• have impaired liver or kidney function



• have systemic lupus erythematosus (SLE), a condition characterised by a rash (especially on the face), hair loss, fever, a feeling of general discomfort and illness and joint pain



• suffer from increased pressure in the skull (intercranial hypertension)



• are sensitive to sunlight or artifical light (e.g. sunbeds).

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Especially:

• penicillins e.g. phenoxymethylpenicillin (to treat infections)



• medicines which can damage the liver (check with your doctor or pharmacist to see if this applies to any medicines you are taking)



• retinoids such as isotretinoin (to treat acne)



• ACE inhibitors such as quinopril (to treat heart conditions)



• oral contraceptives (the pill). Minocycline tablets may make the oral contraceptive pill less effective. You should use additional contraceptive precautions whilst taking tetracycline and for 7 days after stopping



• anticoagulants (to stop the blood clotting)



• ergotamine (to treat migranes)



• ergometrine (to induce abortion or labour)



• diuretics (‘water tablets’) e.g. furosemide



• kaolin (to treat diarrhoea)



• sucralfate and bismuth salts (to treat ulcers)



• medicines such as antacids or other medicines containing aluminium, calcium, iron, magnesium or zinc salts. Do not take at the same time as Minocycline tablets, as absorption of Minocycline may be reduced.

Pregnancy and breast-feeding

If you are pregnant, planning to become pregnant or are breast-feeding tell your doctor or pharmacist before taking any medicine as minocycline could cause permanent discolouration and underdevelopment of tooth enamel.

Driving and using machines

Minocycline tablets can cause lightheadedness, visual disturbances, dizziness, ringing in the ears, a feeling of dizziness or spinning (vertigo). Make sure you are not affected before driving or operating machinery.

Colourant warning

Minocycline tablets (100mg only) contain sunset yellow (E110) which may cause allergic reactions.

Sugar intolerance

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine, as it contains lactose.

Tests

During long term treatment blood, kidney and liver tests will be carried out.

How to take

Always take Minocycline tablets exactly as your doctor has told you. If you are not sure, check with your doctor or pharmacist.

Swallow the tablets whole with a glass of water, while standing or sitting down.

Alcohol

Speak to your doctor before taking Minocycline tablets with alcohol.

• Adults (including the elderly):
  General infections: 200mg a day to be taken in divided doses.
  Acne: 50mg twice a day for a minimum of six weeks.
  Gonorrhoea: initially 200mg, then 100mg every twelve hours for a minimum of four days. Females may require longer-term therapy.
  Preventative treatment in meningitis carriers: 100mg twice a day for five days.
  

• Children over 12 years old: 50mg every twelve hours.
  
  



• Children under 12 years old: Minocycline tablets are not recommended for use in children under 12 years of age, as they can cause permanent discolouration and underdevelopment of tooth enamel.

If you have kidney disease your doctor may give you a lower dose.

If you take more than you should

If you (or someone else) swallow a lot of tablets at the same time, or you think a child may have swallowed any contact your nearest hospital casualty department or tell your doctor immediately. Symptoms of an overdose include dizziness and feeling and being sick.

If you forget to take the tablets

Do not take a double dose to make up for a forgotten dose. If you forget to take a dose take it as soon as you remember it and then take the next dose at the right time.

If you stop taking the tablets

Talk to your doctor before you stop taking the tablets and follow their advice.

Possible side effects

Like all medicines, Minocycline tablets can cause side effects, although not everybody gets them.

Stop taking the tablets immediately and seek urgent medical advice if the following occur:

• allergic reactions (anaphylaxis, hypersensitivity): blood spots, bruising and discolouring to the skin (purpura), shock, flaky skin (exfoliative dermatitis), increase in the number of white blood cells and one or more of the following: inflammation of the liver (hepatitis), inflammation of the lungs caused by an infection (pneumonitis), inflammation of the kidneys, inflammation of the heart muscle (myocarditis) or membrane around the heart (pericarditis), fever, swelling of the lymph nodes.



• Lupus-like syndrome: presence of antinuclear antibodies in the blood, joint pain (arthralgia), inflammation (arthritis) stiffness or swelling of joints and one or more of the following: fever, muscle pain (myalgia), inflammation of the liver (hepatitis), skin rash, inflammation of blood vessels.



• Serum sickness-like syndrome: fever, itchy skin rash, rash, joint pain (arthralgia), inflammation (arthritis) stiffness or swelling of joints, increase in the number of white blood cells.



• raised pressure in the skull: headache, visual problems including blurred vision, “blind” spots, double vision, permanent loss of vision. Bulging of the skull can occur in infants.



• growth of bacteria resistant to tetracyclines: inflammation of the intestines, inflammation of the tongue and mouth, inflammation of the female genitals causing itching, discharge or pain on passing urine, irritation around your bottom, stomach upset.



• development or worsening of existing systemic lupus erythematosus (SLE), symptoms include large areas of red scaly patches on the face, hair loss, weight loss, painful joints and fever.



• symptoms of liver damage: fatigue, weakness, loss of appetite, weight loss, abdominal pain, fever.



• a change in colour of the skin, nails, teeth, mucous membrane of the mouth, bones, thyroid, eyes, breast milk, tears or sweat (hyperpigmentation).

Tell your doctor if the following side effects occur:

• Effects on the stomach and gastrointestinal tract: feeling or being sick, diarrhoea, loss of appetite, underdevelopment of tooth enamel, inflammation of the tongue, mouth or intestines, difficulty swallowing, inflammation or ulceration of the gullet, indigestion, pseudomembranous colitis (watery diarrhoea, fever and cramps).



• Effects on the liver and kidneys: inflammation of the liver (hepatitis), kidneys or pancreas (pancreatitis), liver failure, jaundice (yellowing of the skin or whites of the eyes), abnormal liver function test results, acute kidney failure.



• Effects on the blood: increased levels of urea in the blood, blood vessel inflammation, changes in the numbers and types of your blood cells. If you notice increased bruising, nosebleeds, sore throats, infections, excessive tiredness, breathlessness on exertion or abnormal paleness of the skin, you should tell your doctor who may want you to have a blood
  test



• Effects on the nervous system: dizziness, headache, tingling or pins and needles in the hands and feet, feeling of dizziness or spinning (vertigo), decreased sensitivity to touch, fits, drowsiness,



• Effects on the skin: hair loss, skin reactions including red patches (erythema multiforme), skin rash which may be itchy with or without pale or red raised patches, swelling of the face lips tongue or throat, severe skin rash with flushing, fever, blisters or ulcers (Stevens-Johnson syndrome), a severe rash with reddening, peeling and swelling of the skin that resembles burns (toxic epidermal necrolysis), red lumps on the legs (erythema nodosum).



• Effects on breathing: cough, difficulty breathing, worsening of asthma, increase in the number of white blood cells in the lungs.



• Effects on muscles and bones: joint pain (arthralgia), inflammation (arthritis) stiffness or swelling of joints, muscle pain (myalgia).



• Other: sensitivity to sunlight or artificial light (e.g. sunbeds), impaired
  hearing, ringing in the ears, thrush around your bottom, genital area or mouth, inflammation of male genitals, changes in thyroid function, systemic lupus erythematosus (SLE), if you already suffer from SLE Minocycline tablets may make your condition worse.

If you notice any side effects, they get worse, or if you notice any not listed, please tell your doctor or pharmacist.

How to store

Keep out of the reach and sight of children.

Store below 25°C in a dry place.

Protect from light.

Do not use Minocycline tablets after the expiry date stated on the label/carton/bottle. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Minocycline tablets contain

• Each tablet contains the active substance (the ingredient that makes the tablets work) minocycline hydrochloride PhEur equivalent to 50mg or 100mg anhydrous minocycline.



• 50mg tablets contain: hydroxypropylcellulose (E463), maize starch, magnesium stearate, lactose and methylated spirits. The tablet coating contains hypromellose (E464), propylene glycol, purified talc, methylated spirits, titanium dioxide (E171), iron oxides (E172).



• 100mg tablets contain: hydroxypropylcellulose (E463), maize starch, magnesium stearate, lactose and methylated spirits. The tablet coating contains hypromellose (E464), propylene glycol, purified talc, methylated spirits, titanium dioxide (E171), sunset yellow (E110) and quinoline yellow (E104).

What Minocycline tablets look like and contents of the pack

50mg tablets are beige, circular, biconvex, film-coated tablets.

100mg tablets are orange, circular, biconvex, film-coated tablets.

Pack size is 28.

Marketing Authorisation Holder and manufacturer

Actavis

Barnstaple

EX32 8NS

UK

This leaflet was last revised in September 2007.

Actavis

Barnstaple

EX32 8NS

UK

50130559

Flurandrenolide

Class: Anti-inflammatory Agents
ATC Class: D07AB
VA Class: DE200
Chemical Name: Pregn-4-ene-3,20-dione,6-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis (oxy)]-,(6α,11β,16α)-
Molecular Formula: C₂₄H₃₃FO₆
CAS Number: 1524-88-5
Brands: Cordran

Introduction

A synthetic fluorinated corticosteroid.^a

Uses for Flurandrenolide

Corticosteroid-responsive Dermatoses

Relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.^{a c d e}

Generally most effective in acute or chronic dermatoses (e.g., seborrheic or atopic dermatitis, localized neurodermatitis, anogenital pruritus, psoriasis, late phase of allergic contact dermatitis, inflammatory phase of xerosis).^b

Topical therapy generally preferred over systemic therapy; fewer associated adverse systemic effects.^b

Topical therapy generally only controls manifestations of dermatoses; eliminate cause if possible.^b

Topical efficacy may be increased by using a higher concentration or occlusive dressing therapy. (See Administration with Occlusive Dressing under Dosage and Administration.)^b

Response may vary from one topical corticosteroid preparation to another.^b

Anti-inflammatory activity may vary considerably depending on the vehicle, drug concentration, site of application, disease, and individual patient.^b

Flurandrenolide 0.05% ointment is considered to have high-range potency.^b

Flurandrenolide 0.05% cream is considered to have medium-range potency.^b

Flurandrenolide Dosage and Administration

General

• 
  

  Consider location of the lesion and the condition being treated when choosing a dosage form.^b

  
  


• 
  

  Creams are suitable for most dermatoses, but ointments may also provide some occlusion and are usually used for the treatment of dry, scaly lesions.^b Tape is most suitable for dry, scaling localized lesions.^d

  
  


• 
  

  Lotions are probably best for treatment of weeping eruptions, especially in areas subject to chafing (e.g., axilla, foot, groin).^b Lotions may be used on hairy areas, particularly the scalp.^b

  
  


• 
  

  Formulation affects percutaneous penetration and subsequent activity; extemporaneous preparation or dilution of commercially available products with another vehicle may decrease effectiveness.^b

  
  


• 
  

  Patients applying a topical corticosteroid to a large surface area and/or to areas under occlusion should be evaluated periodically for evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression by appropriate endocrine testing^{b c d e} (e.g., ACTH stimulation,^{b c d e} plasma cortisol,^b urinary free cortisol^{b c d e} ). (See Hypothalamic-Pituitary-Adrenal Axis Suppression and also Systemic Effects, under Cautions.)

  
  

Administration

Topical Administration

For dermatologic use only; avoid contact with eyes.^{c d e}

Apply creams, ointments, and lotions topically to the skin or scalp.^{c e}

The area of skin to be treated may be thoroughly cleansed before topical application to reduce the risk of infection; however, some clinicians believe that, unless an occlusive dressing is used, cleansing of the treated area is unnecessary and may be irritating.^b

Apply cream or lotion sparingly in a thin film and rub gently into the affected area.^{a c e} Apply ointment in a thin film.^c

After a favorable response is achieved, frequency of application or concentration (strength) may be decreased to the minimum necessary to maintain control and to avoid relapse; discontinue if possible.^b

Tape

Gently clean affected area using germicidal soap or cleanser to remove scales, crusts, dried exudates, and previously used ointments or creams.^d

Shave or clip hair in treatment area; dry skin completely before applying tape.^d

Cut tape slightly larger than area to be covered, rounding off corners; do not tear tape.^d

Remove paper backing; apply tape, keeping skin smooth; press into place.^d

If ends of tape loosen prematurely, trim off ends and replace with fresh tape.^d

When replacing tape, cleanse skin and allow to dry for 1 hour before applying new tape.^d

Administration with Occlusive Dressing

Occlusive dressings may be used for severe or resistant dermatoses (e.g., psoriasis).^{b c e} (See Occlusive Dressings under Cautions.)

Soak or wash the affected area to remove scales; apply a thin film of cream, ointment, or lotion; rub gently into the lesion;^{b c e} and apply another thin film.^b Cover affected area with a thin, pliable plastic film and seal it to adjacent normal skin with adhesive tape or hold in place with a gauze or elastic bandage.^{b c e}

If affected area is moist, incompletely seal the edges of the plastic film or puncture the film to allow excess moisture to escape.^b For added moisture in dry lesions, apply cream or lotion and cover with a dampened cloth before the plastic film is applied^{c e} or briefly soak the affected area in water before application of the drug and plastic film.^b

Thin polyethylene gloves may be used on the hands and fingers, plastic garment bags may be used on the trunk or buttocks, a tight shower cap may be used for the scalp, or whole-body suits may be used instead of plastic film to provide occlusion.^{b c e}

Frequency of occlusive dressing changes depends on the condition being treated; cleansing of the skin and reapplication of the corticosteroid are essential at each dressing change.^b

Occlusive dressing usually is left in place for 12–24 hours and therapy is repeated as needed.^b Although occlusive dressing may be left in place for 3–4 days at a time in resistant conditions,^{c e} most clinicians recommend intermittent use of occlusive dressings for 12 hours daily to reduce the risk of adverse effects (particularly infection) and systemic absorption and for greater convenience.^b

Manufacturer recommends continuing treatment for a few days after lesion clearing to prevent relapse; if relapse does occur, resinstituting treatment may cause remission.^{c e}

The drug and an occlusive dressing may be used at night, and the drug or a bland emollient may be used without an occlusive dressing during the day.^{b c e}

In patients with extensive lesions, sequential occlusion of only one portion of the body at a time may be preferable to whole-body occlusion.^b (See Occlusive Dressings under Cautions.)

Dosage

Pediatric Patients

Administer the least amount of topical preparations that provide effective therapy.^{b c d e} (See Pediatric Use under Cautions.)

Corticosteroid-responsive Dermatoses

Topical

Apply cream, ointment, or lotion sparingly 2–3 times daily.^{a c e}

Replace tape every 12 hours;^{a d} may be left in place for 24 hours if well tolerated and adheres satisfactorily.^d

If necessary, may use tape at night only and remove during the day.^d

Adults

Corticosteroid-responsive Dermatoses

Topical

Apply cream, ointment, or lotion sparingly 2–3 times daily.^{c e}

Replace tape every 12 hours; may be left in place for 24 hours if well tolerated and adheres satisfactorily.^d

If necessary, may use tape at night only and remove during the day.^d

Special Populations

No special population dosage recommendations at this time.^{c d e}

Cautions for Flurandrenolide

Contraindications

• 
  

  Known hypersensitivity to flurandrenolide or any ingredient in the formulation.^{c d e}

  
  


• 
  

  Tape: Lesions exuding serum or in intertriginous areas.^d

  
  

Warnings/Precautions

Sensitivity Reactions

Allergic contact dermatitis may manifest as failure to heal rather than irritation as occurs with other topical preparations that do not contain corticosteroids; confirm with diagnostic patch testing.^b

General Precautions

Hypothalamic-Pituitary-Adrenal Axis Suppression

Topically applied corticosteroids can be absorbed in sufficient amounts to reversibly suppress the HPA axis.^{b c d e}

Perform periodic HPA-axis evaluation by appropriate testing (e.g., ACTH stimulation,^{b c d e} morning plasma cortisol,^b urinary free cortisol^{b c d e} ), especially in patients applying a topical corticosteroid to a large surface area or to areas under occlusion.^{b c d e}

If HPA-axis suppression occurs, withdraw the drug, reduce the frequency of application, and/or substitute a less potent corticosteroid.^{b c d e}

HPA-axis function recovery generally is prompt and complete following drug discontinuance.^{b c d e}

Rarely, glucocorticosteroid insufficiency may require systemic corticosteroid therapy.^{b c d e}

Systemic Effects

Systemic absorption following topical administration may result in manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients.^{b c d e}

Adverse systemic effects may occur when corticosteroids are used on large areas of the body, for prolonged periods of time, with an occlusive dressing, and/or concurrently with other corticosteroid-containing preparations.^b

Infants and children may be more susceptible to adverse systemic effects. ^{c d e} (See Pediatric Use under Cautions.)

Local Effects

Possible adverse local reactions (e.g., burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, miliaria); may occur more frequently with the use of occlusive dressings, especially with prolonged therapy.^b

Prolonged use of topical corticosteroids may cause atrophy of the epidermis and subcutaneous tissue;^b these effects are most likely to occur (even with short-term use) in intertriginous (e.g., axilla, groin), flexor, and facial areas.^b

If irritation occurs, discontinue drug and institute appropriate therapy.^{b c d e}

Skin Infection

If concurrent skin infection is present or develops, initiate appropriate anti-infective therapy.^{b c d e} If infection does not respond promptly, consult clinician and discontinue topical corticosteroid therapy until the infection has been controlled.^{b c d e}

When topical corticosteroids and topical anti-infectives are used concomitantly, consider that the corticosteroid may mask clinical signs of bacterial, fungal, or viral infections; prevent recognition of ineffectiveness of the anti-infective; or suppress hypersensitivity reactions to ingredients in the formulation.^b In addition, consider the cautions, precautions, and contraindications associated with the anti-infective.^b (See Occlusive Dressings under Cautions.)

Some manufacturers state that topical corticosteroids are contraindicated in patients with tuberculosis of the skin, dermatologic fungal infections, and cutaneous or systemic viral infection (including vaccinia and varicella and herpes simplex of the eye or adjacent skin).^b However, most clinicians believe topical corticosteroids can be used with caution if the infection is treated.^b

Occlusive Dressings

Adverse systemic corticosteroid effects may occur with use of occlusive dressings on large areas of the body and for prolonged periods of time; monitor accordingly.^b (See Hypothalamic-Pituitary-Adrenal Axis Suppression and also Systemic Effects, under Cautions.)

Adverse local reactions may occur more frequently with the use of occlusive dressings, especially with prolonged therapy.^b (See Local Effects under Cautions.)

Do not use occlusive dressings on weeping or exudative lesions.^{b c}

Do not use occlusive dressings in patients with primary skin infection.^b

Remove occlusive dressings covering large areas if body temperature increases; thermal homeostasis may be impaired.^{b c}

Restrict use in hospitalized patients; increased hazard of secondary infection from resistant strains of staphylococci.^{c e}

If infection develops, discontinue use of occlusive dressings and institute appropriate antimicrobial therapy.^{c e} (See Skin Infection under Cautions.)

Use plastic occlusive material with care to avoid the risk of suffocation.^{b c e}

If miliaria or folliculitis occurs, discontinue use of occlusive dressing; may continue corticosteroid treatment.^{c e}

Do not use flammable plastic films as occlusive material.^{c e}

Specific Populations

Pregnancy

Category C.^{c d e}

Lactation

Not known whether topical flurandrenolide is distributed into milk.^{c d e} Caution advised if topical flurandrenolide is used.^{c d e}

Pediatric Use

Tight-fitting diapers or plastic pants should not be used on a child being treated in the diaper area, since such garments may constitute occlusive dressings.^{c d e}

Children are more susceptible to topical corticosteroid-induced HPA-axis suppression and Cushing's syndrome than mature individuals because of a greater skin surface area-to-body weight ratio,^{b c d e} especially when topical corticosteroids are applied to >20% of body surface area.^f The risk of adrenal suppression appears to increase with decreasing age.^b (See Systemic Effects under Cautions.)

Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol concentrations, and lack of response to corticotropin (ACTH) stimulation.^{b c d e}

Children also are at greater risk of glucocorticoid insufficiency during and/or after withdrawal of treatment.^d

Intracranial hypertension has occurred in children; manifestations include bulging fontanelles, headaches, and bilateral papilledema.^{b c d e}

Topical corticosteroid therapy in children should be limited to the minimum amount necessary for therapeutic efficacy; chronic topical corticosteroid therapy may interfere with growth and development.^{b c d e}

Common Adverse Effects

Burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, miliaria.^{c d e}

Interactions for Flurandrenolide

Specific Drugs and Laboratory Tests

Drug or Test	Interaction
Nitroblue-tetrazolium test for bacterial infection	Concurrent use of corticosteroids reportedly may result in false-negative resultsb

Flurandrenolide Pharmacokinetics

Absorption

Bioavailability

Topically applied flurandrenolide can be absorbed through normal intact skin.^{b c d e}

Percutaneous penetration of corticosteroids following topical application to the skin varies among individuals and may be increased by occlusive dressings, high corticosteroid concentrations, and certain vehicles.^{b c d e}

Only minimal amounts of topical corticosteroid reach the dermis and subsequently the systemic circulation after application to most normal skin areas; more absorption occurs from the scrotum, axilla, eyelid, face, and scalp than from the forearm, knee, elbow, palm, and sole.^b

Absorption is markedly increased by loss of the skin’s keratin layer and by inflammation and/or diseases of the epidermal barrier (e.g., psoriasis, eczema).^{b c d e}

Distribution

Extent

Not known whether topical flurandrenolide is distributed into milk.^{c d e}

Elimination

Metabolism

Once absorbed through the skin, topically applied corticosteroids are metabolized primarily in the liver.^{b c d e}

Elimination Route

Topical corticosteroids and metabolites are excreted by the kidneys and, to a lesser extent, in bile.^{b c d e}

Stability

Storage

Topical

Cream, Ointment, and Lotion

15–30°C;^{c e} avoid freezing.^a

Tape

25°C (may be exposed to 15–30°C).^d

ActionsActions

• 
  

  Ointment has high-range corticosteroid activity; cream has medium-range corticosteroid activity.^b

  
  


• 
  

  Precise mechanism of action for topical anti-inflammatory activity is unknown; therapeutic benefit in the management of corticosteroid-responsive dermatoses mediated primarily through anti-inflammatory, antipruritic, and vasoconstrictive actions.^{b c d e}

  
  


• 
  

  Anti-inflammatory effects may occur through stabilization of cellular and lysosomal membranes, preventing release of proteolytic enzymes.^{c d e}

  
  


• 
  

  Decreases inflammation by stabilizing leukocyte lysosomal membranes, preventing release of destructive acid hydrolases from leukocytes; inhibiting macrophage accumulation in inflamed areas; reducing leukocyte adhesion to capillary endothelium; reducing capillary wall permeability and edema formation; decreasing complement components; antagonizing histamine activity and release of kinin from substrates; reducing fibroblast proliferation, collagen deposition, and subsequent scar tissue formation; and possibly by other mechanisms as yet unknown.^b

  
  


• 
  

  Evaporation of water from lotion vehicle produces cooling effect.^e

  
  


• 
  

  Tape is vehicle and occlusive dressing; retains insensible perspiration resulting in hydration of stratum corneum and improved drug diffusion.^d Tape protects skin and acts as mechanical splint for fissures; also provides sustained action by preventing drug removal.^d

  
  

Advice to Patients

• 
  

  Importance of using only as directed, only for the disorder for which it was prescribed, and for no longer than prescribed; avoid contact with the eyes and only apply externally as directed.^{c d e} (See Topical Administration under Dosage and Administration.)

  
  


• 
  

  Importance of informing patients that treated areas of the skin should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by a clinician.^{c d e}

  
  


• 
  

  Importance of reporting any local adverse reactions, especially those occurring under occlusive bandage, to a clinician.^{b c d e}

  
  


• 
  

  Importance of informing parents of children not to use diapers or plastic pants on children being treated in the diaper area as these garments may constitute occlusive dressings.^{c d}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{c d e}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{c d e}

  
  


• 
  

  Importance of advising patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Flurandrenolide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Topical	Cream	0.025% and 0.05%	Cordran SP (with propylene glycol)	Watson
	Dressing	4 mcg/cm2 roll and patch	Cordran Tape	Watson
	Lotion	0.05%	Cordran (with benzyl alcohol)	Watson
	Ointment	0.025% and 0.05%	Cordran	Watson

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions January 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

a. AHFS drug information 2007. McEvoy GK, ed. Flurandrenolide. Bethesda, MD: American Society of Health-Systems Pharmacists; 2007: 3531.

b. AHFS drug information 2007 McEvoy GK, ed. Topical corticosteroids general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2005:3423–5.

c. Oclassen Dermatologics. Cordran(flurandrenolide) cream and ointment prescribing information. Corona, CA; 2006 Jun.

d. Oclassen Dermatologics. Cordran (flurandrenolide) tape prescribing information. Corona, CA; 2003 Mar.

e. Oclassen Dermatologics. Cordran (flurandrenolide) lotion prescribing information. Corona, CA; 2006 Jun.

f. Connetics Corporation. Verdeso (desonide) aerosol, foam prescribing information. Palo Alto, CA; 2006 Oct.

More Flurandrenolide resources

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

Compare Flurandrenolide with other medications

• Atopic Dermatitis
• Dermatitis
• Eczema
• Psoriasis

Leustatin

Generic Name: cladribine (Intravenous route)

KLAD-ri-been

Intravenous route(Solution)

Suppression of bone marrow function, which is usually reversible and appears to be dose dependent, should be anticipated with cladribine. Serious neurological toxicity (including irreversible paraparesis and quadraparesis) has been reported in patients who received cladribine injection by continuous infusion at high doses (4 to 9 times the recommended dose for hairy cell leukemia). Neurologic toxicity appears to demonstrate a dose relationship; however, severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens. Acute nephrotoxicity has been observed with high doses of cladribine (4 to 9 times the recommended dose for hairy cell leukemia), especially when given concomitantly with other nephrotoxic agents/therapies .

Commonly used brand name(s)

In the U.S.

• Leustatin

Available Dosage Forms:

• Solution

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Antimetabolite

Chemical Class: Purine Nucleoside Analog

Uses For Leustatin

Cladribine belongs to the group of medicines called antimetabolites. It is used to treat hairy cell leukemia, a cancer of the blood and bone marrow. It is also sometimes used to treat other kinds of cancer, as determined by your doctor.

Cladribine interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by cladribine, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects may not be serious but may cause concern. Some effects may not occur for months or years after the medicine is used.

Before you begin treatment with cladribine, you and your doctor should talk about the good this medicine will do as well as the risks of using it.

Cladribine is to be administered only by or under the immediate supervision of your doctor.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, cladribine is used in certain patients with the following conditions:

• Cancer of the blood and lymph system


• Waldenström's macroglobulinemia (a certain type of cancer of the blood)

Before Using Leustatin

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

Allergies

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

Pediatric

There is no specific information comparing use of cladribine in children with use in other age groups. However, cladribine has been reported to be tested in children with certain types of cancers of the blood.

Geriatric

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

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Rotavirus Vaccine, Live

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Adenovirus Vaccine Type 4, Live


• Adenovirus Vaccine Type 7, Live


• Bacillus of Calmette and Guerin Vaccine, Live


• Influenza Virus Vaccine, Live


• Measles Virus Vaccine, Live


• Mumps Virus Vaccine, Live


• Rotavirus Vaccine, Live


• Rubella Virus Vaccine, Live


• Smallpox Vaccine


• Typhoid Vaccine


• Varicella Virus Vaccine


• Yellow Fever Vaccine

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Chickenpox (including recent exposure) or


• Herpes zoster (shingles)—Risk of severe disease affecting other parts of the body

• Gout (history of) or


• Kidney stones (history of)—Cladribine may increase levels of uric acid in the body, which can cause gout or kidney stones

• Infection—Cladribine may decrease your body's ability to fight infection

Proper Use of Leustatin

This medicine may cause mild nausea and may also cause vomiting. However, it is very important that you continue to receive the medicine even if you begin to feel ill. Ask your health care professional for ways to lessen these effects.

Dosing

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

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

Precautions While Using Leustatin

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to check for unwanted effects.

While you are being treated with cladribine, and after you stop treatment with it, do not have any immunizations (vaccinations) without your doctor's approval. Cladribine may lower your body's resistance and there is a chance you might get the infection the immunization is meant to prevent. In addition, other persons living in your household should not take oral polio vaccine since there is a chance they could pass the polio virus on to you. Also, avoid persons who have taken oral polio vaccine within the last several months. Do not get close to them and do not stay in the same room with them for very long. If you cannot take these precautions, you should consider wearing a protective face mask that covers the nose and mouth.

Cladribine can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections, colds, or flu. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.


• Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on your skin.


• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.


• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.


• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.


• Avoid contact sports or other situations where bruising or injury could occur.

Leustatin Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Some side effects will have signs or symptoms that you can see or feel. Your doctor may watch for others by doing certain tests.

Also, because of the way cancer medicines act on the body, there is a chance that they might cause other unwanted effects that may not occur until months or years after the medicine is used. These delayed effects may include certain types of cancer. Discuss these possible effects with your doctor.

Check with your doctor immediately if any of the following side effects occur:

More common

• Black, tarry stools


• blood in urine


• cough or hoarseness, accompanied by fever or chills


• fever


• lower back or side pain, accompanied by fever or chills


• painful or difficult urination, accompanied by fever or chills


• pinpoint red spots on skin


• unusual bleeding or bruising

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

More common

• Skin rash

Less common

• Pain or redness at place of injection


• shortness of breath


• stomach pain


• swelling of feet or lower legs


• unusually fast heartbeat

This medicine may also cause the following side effects that your doctor will watch out for:

More common

• Anemia


• low white cell counts in blood

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

More common

• Headache


• loss of appetite


• nausea


• unusual tiredness


• vomiting

Less common

• Constipation


• diarrhea


• dizziness


• general feeling of discomfort or illness


• itching


• muscle or joint pain


• sweating


• trouble in sleeping


• weakness

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

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

See also: Leustatin side effects (in more detail)

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More Leustatin resources

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

• Leustatin Prescribing Information (FDA)


• Leustatin MedFacts Consumer Leaflet (Wolters Kluwer)


• Leustatin Concise Consumer Information (Cerner Multum)


• Leustatin Monograph (AHFS DI)


• Cladribine Prescribing Information (FDA)


• Cladribine Professional Patient Advice (Wolters Kluwer)

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