Rectogesic 4 mg / g Rectal Ointment

1. Name Of The Medicinal Product

Rectogesic 4 mg/g Rectal Ointment.

2. Qualitative And Quantitative Composition

Glyceryl trinitrate: 4 mg/g.

One gram of rectal ointment contains 40 mg Glyceryl trinitrate in propylene glycol corresponding to 4 mg Glyceryl trinitrate (GTN). The delivered dose from 375 mg of this formulation is approximately 1.5 mg GTN.

The ointment also contains 36 mg Propylene Glycol, and 140 mg Lanolin, per gram rectal ointment.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Rectal ointment.

Off-white smooth opaque ointment formulation.

4. Clinical Particulars

4.1 Therapeutic Indications

Rectogesic 4 mg/g Rectal Ointment is indicated for relief of pain associated with chronic anal fissure.

In the clinical development of the drug, a modest effect has been shown on improvements in average daily pain intensity (see Section 5.1).

4.2 Posology And Method Of Administration

Route of administration: rectal use

Adults:

A finger covering, such as cling film or a finger cot, may be placed on the finger to be used to apply the ointment. (Finger cots to be obtained separately from local pharmacy or surgical supplies retailer or cling film from local store.) The finger is placed along side a 2.5cm dosing line which is provided on the outside carton in which Rectogesic is supplied, and a strip of ointment the length of the line is expressed onto the end of the finger by gently squeezing the tube. The amount of ointment expressed is approximately 375 mg (1.5 mg GTN). The covered finger is then gently inserted into the anal canal to the distal interphalangeal joint of the finger and applied circumferentially to the anal canal.

The dose delivered from the 4 mg/g ointment is 1.5 mg glyceryl trinitrate. The dose is to be applied intra-anally every twelve hours. Treatment may be continued until the pain abates, up to a maximum of 8 weeks.

Rectogesic should be used following conservative treatment failure for acute symptoms of anal fissure.

Elderly:

No specific information concerning the usage of Rectogesic in the elderly is available

Patients with Hepatic or Renal Impairment

No specific information concerning the usage of Rectogesic in patients with hepatic or renal impairment is available

Children and Adolescents:

Rectogesic is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.

4.3 Contraindications

Hypersensitivity to the active substance “glyceryl trinitrate” or to any of the excipients or idiosyncratic reactions to other organic nitrates.

Concomitant treatment with sildenafil citrate, tadalafil, vardenafil and with nitric oxide (NO) donors, such as other long-acting GTN products, isosorbide dinitrate and amyl or butyl-nitrite.

Postural hypotension, hypotension or uncorrected hypovolaemia as the use of glyceryl trinitrate in such states could produce severe hypotension or shock.

Increased intracranial pressure (e.g. head trauma or cerebral haemorrhage) or inadequate cerebral circulation.

Migraine or recurrent headache.

Aortic or mitral stenosis.

Hypertrophic obstructive cardiomyopathy.

Constrictive pericarditis or pericardial tamponade.

Marked anaemia.

Closed-angle glaucoma.

4.4 Special Warnings And Precautions For Use

The risk/benefit ratio of Rectogesic has to be established on an individual basis. In some patients, following treatment with Rectogesic, severe headache can occur. In some cases re-evaluation of the correct dosing is suggested. In patients where the risk benefit ratio is deemed to be negative, treatment with Rectogesic should be withdrawn under the guidance of a physician and other therapeutic or surgical interventions should be initiated.

Rectogesic should be used with caution in patients who have severe hepatic or renal disease.

Excessive hypotension, especially for prolonged periods of time, must be avoided because of possible deleterious effects on the brain, heart, liver and kidney from poor perfusion and the attendant risk of ischaemia, thrombosis and altered function of these organs. Patients should be advised to change position slowly when changing from lying or sitting to upright to minimize postural hypotension. This advice is particularly important for those patients with low blood volume and under diuretic treatment. Paradoxical bradycardia and increased angina pectoris may accompany glyceryl trinitrate-induced hypotension. The elderly may be more susceptible to the development of postural hypotension, particularly on sudden rising. No specific information concerning the usage of Rectogesic in the elderly is available.

Alcohol may enhance the hypotensive effects of glyceryl trinitrate.

If the physician elects to use glyceryl trinitrate ointment for patients with acute myocardial infarction or congestive heart failure, careful clinical and haemodynamic monitoring must be used to avoid the potential hazards of hypotension and tachycardia.

If bleeding associated with haemorrhoids increases, treatment should be stopped.

This formulation contains propylene glycol and lanolin which may cause skin irritations and skin reactions (e.g. contact dermatitis).

If anal pain persists, differential diagnosis may be required to exclude other causes of the pain.

Glyceryl trinitrate can interfere with the measurement of catecholamines and vanilmandelic acid in urine as it increases the excretion of these substances.

Concomitant treatment with a number of other medicinal products should be handled with caution. Please refer to section 4.5 for specific information.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant treatment with other vasodilators, calcium channel blockers, ACE inhibitors, beta blockers, diuretics, anti-hypertensives, tricyclic anti-depressants and major tranquillisers, as well as the consumption of alcohol, may potentiate the blood pressure lowering effects of Rectogesic. Therefore, concomitant treatment with these medications should be carefully considered before treatment with Rectogesic is initiated.

The hypotensive effect of nitrates are potentiated by concurrent administration of phosphodiesterase inhibitors, e.g. sildenafil, tadalafil and vardenafil (see Section 4.3).

Rectogesic is contraindicated for concomitant treatment with, nitric oxide (NO) donors such as isosorbide dinitrate and amyl or butyl-nitrite (see Section 4.3).

Acetyl cysteine may potentiate the vasodilatory effects of glyceryl trinitrate.

Concomitant treatment with heparin leads to a decrease in heparin efficacy. Close monitoring of blood coagulation parameters is necessary and the dose of heparin has to be adapted accordingly. After withdrawal of Rectogesic there may be an abrupt increase in PTT. In this case reduction of heparin dosage may be necessary.

Concurrent administration of glyceryl trinitrate may cause a reduction of the thrombolytic activity of alteplase.

Co-administration of Rectogesic with dihydroergotamine may increase the bioavailability of dihydroergotamine and lead to coronary vasoconstriction. The possibility that the ingestion of acetylsalicylic acid and non-steroidal anti-inflammatory drugs might diminish the therapeutic response to Rectogesic cannot be excluded.

4.6 Pregnancy And Lactation

Pregnancy: There are no adequate data from the use of glyceryl trinitrate in pregnant women. Animal studies are inconclusive with respect to effects on pregnancy embryonal/foetal parturition and postnatal development (see Section 5.3). Rectogesic should not be used during pregnancy.

Lactation: It is not known whether glyceryl trinitrate is excreted in human milk. Due to the potential harmful effects on the breast fed child (see Section 5.3), the use of Rectogesic is not recommended during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effect on the ability to drive and use machines have been performed with Rectogesic. Rectogesic may cause dizziness, light-headedness, blurred vision, headache or tiredness in some patients, especially on first use. Patients should be cautioned about driving or operating machinery while using Rectogesic.

4.8 Undesirable Effects

In patients treated with Rectogesic 4 mg/g Rectal Ointment, the most common treatment related adverse reaction was dose-related headache which occurred with an incidence of 57%.

Adverse reactions from clinical studies are displayed by system organ class in the table below. Within the system organ class, the adverse reactions are listed by frequency using the following groupings: very common (> 1/10), common (>1/100 <1/10), uncommon (>1/1000 <1/100).

System Organ Class	Frequency	Adverse Reaction
Nervous system disorder	Very common	Headache
	Common	Dizziness
Gastrointestinal disorders	Common	Nausea
	Uncommon	Diarrhoea, anal discomfort, vomiting, rectal bleeding, rectal disorder
Skin and subcutaneous tissue disorders	Uncommon	Pruritus, anal burning and itching
Cardiovascular system disorders	Uncommon	Tachycardia

Adverse reactions to glyceryl trinitrate 2% ointment (used in the prophylaxis of angina pectoris) are generally dose-related and almost all of these reactions are the result of vasodilator activity. Headache, which may be severe, is the most commonly reported side effect. In the Phase III clinical trials with Rectogesic 4 mg/g Rectal Ointment the incidence of mild, moderate and severe headache was 18%, 25% and 20%. Patients with a previous history of migraine or recurrent headache were at a higher risk of developing headache during treatment (see Section 4.3). Headache may be recurrent with each daily dose, especially at higher doses. Headache can be treated with mild analgesics e.g. paracetamol and in general is reversible on discontinuation of treatment.

Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy. Syncope, crescendo angina and rebound hypertension have been reported but are uncommon. Allergic reactions to glyceryl trinitrate are uncommon, and the great majority of those reported have been cases of contact dermatitis or fixed drug eruptions occurring in patients receiving glyceryl trinitrate in ointments or patches. There have been a few reports of genuine anaphylactoid reactions and these reactions can probably occur in patients receiving glyceryl trinitrate by any route. Extremely rarely, ordinary doses of organic nitrates have caused methaemoglobinaemia in normal–seeming patients. Flush has been observed as a rare adverse reaction for other products containing glyceryl trinitrate.

4.9 Overdose

Accidental overdose of Rectogesic may result in hypotension and reflex tachycardia. No specific antagonist of the vasodilator effects of nitroglycerin is known, and no intervention has been subjected to controlled study as a therapy for nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilation and arterial hypovolaemia, prudent therapy in this situation should be directed toward increasing central fluid volume. Passive elevation of the patient's legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary. In exceptional cases of severe hypotension or shock, resuscitation measures may be needed.

Excessive dosage may also give rise to methaemoglobinaemia. This should be treated with methylene blue infusion.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Muscle relaxants

ATC Code: C05AE01

The principal pharmacologic action of glyceryl trinitrate is mediated via the release of nitric oxide. When glyceryl trinitrate ointment is applied by the intra-anal route, the internal anal sphincter becomes relaxed.

Hypertonicity of the internal but not the external anal sphincter is a predisposing factor in the formation of anal fissures. The blood vessels to the anoderm course through the internal anal sphincter (IAS). Therefore hypertonicity of the IAS may thereby decrease blood flow and cause ischaemia to this region.

Distension of the rectum results in the anorector inhibitory reflex and relaxation of the internal anal sphincter. The nerves mediating this reflex lie in the wall of the gut. Release of the neurotransmitter NO from nerves of this type play a significant role in the physiology of the internal anal sphincter. Specifically, NO mediates the anorector inhibitory reflex in man, relaxing the IAS.

The link between IAS hypertonicity and spasm and the presence of an anal fissure has been established. Patients with chronic anal fissure have a significantly higher mean maximum resting anal pressure than controls and anodermal blood flow in chronic anal fissure patients was significantly lower than in controls. In patients whose fissures healed following a sphincterotomy, a reduction in anal pressure and improvement in anodermal blood flow was demonstrated, providing further evidence for the ischaemic nature of anal fissure. Topical application of a NO donor (glyceryl trinitrate) relaxes the anal sphincter, resulting in a reduction of anal pressure and an improvement in anoderm blood flow.

Effect on pain

In three Phase III clinical trials Rectogesic 4 mg/g Rectal Ointment has been shown to improve the average daily pain intensity associated with chronic anal fissure compared with placebo, measured using a 100mm visual analogue scale. In the first study, Rectogesic 4 mg/g Rectal Ointment decreased average daily pain intensity over 21 days by 13.3mm (baseline 39.2mm) compared to 4.3mm (baseline 25.7mm) for placebo (p<0.0063) and over 56 days by 18.8mm compared to 6.9mm (p<0.0001), respectively. This corresponds to a treatment effect (difference between the percentage change for Rectogesic and placebo) of 17.2% over 21 days and 21.1% over 56 days. In the second study, Rectogesic 4 mg/g Rectal Ointment decreased average daily pain intensity over 21 days by 11.1mm (baseline 33.4mm) compared to 7.7mm (baseline 34.0mm) for placebo (p<0.0388) and over 56 days by 17.2mm compared to 13.8mm (p<0.0039), respectively. This corresponds to a treatment effect of 10.6% over 21 days and 10.9% over 56 days. In the third study, Rectogesic 4 mg/g Rectal Ointment decreased average daily pain intensity over 21 days by 28.1mm (baseline 55.0mm) compared to 24.9mm (baseline 54.1mm) for placebo (p<0.0489) and over 56 days by 35.2mm compared to 33.8mm (p<0.0447), respectively. This corresponds to a treatment effect of 5.1% over 21 days and 1.5% over 56 days.

Effect on healing

In all three studies, healing of anal fissures in patients treated with Rectogesic 4 mg/g Rectal Ointment was not statistically different from placebo. Rectogesic is not indicated for healing of chronic anal fissure.

5.2 Pharmacokinetic Properties

The volume of distribution of glyceryl trinitrate is about 3 L/kg and is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about 3 minutes. The observed clearance rates (close to 1 L/kg/min) greatly exceed hepatic blood flow. The known sites of extrahepatic metabolism include red blood cells and vascular walls. The initial products in the metabolism of glyceryl trinitrate are inorganic nitrate and the 1,2 and 1,3-dinitroglycerols. The dinitrates are less effective vasodilators than glyceryl trinitrate, but they are longer lived in the serum. Their contribution to the relaxation of the internal anal sphincter is unknown. The dinitrates are further metabolised to non-vasoactive mononitrates and ultimately to glycerol and carbon dioxide. In six healthy subjects, the average bioavailability of glyceryl trinitrate applied to the anal canal as a 0.2% ointment was approximately 50% of the 0.75 mg dose.

5.3 Preclinical Safety Data

Repeat Dose Toxicity

No systemic toxicity studies have been conducted with Rectogesic. Published data suggest that high oral doses of glyceryl trinitrate may have toxic effects (methaemoglobinaemia, testicular atrophy and aspermatogenesis) in long term treatment. However, these findings represent no special hazards for humans under the conditions of therapeutic use.

Mutagenicity and carcinogenicity

Data from preclinical studies with GTN indicate genotoxic effects in the repair deficient S. typhimurium strain TA1535 only and carcinogenic effects. However, an increased carcinogenic risk under the conditions of therapeutic use is considered very unlikely.

Reproductive Toxicity

Reproductive toxicity studies, in rats and rabbits with intravenous, intraperitoneal, and dermal administration of glyceryl trinitrate did not show any adverse effects on fertility or embryonic development at dosages which did not induce parental toxicity. No teratogenicity had been observed. In rats foetotoxic effects (decreased birth weights) were seen at dosages above 1 mg/kg/d (i.p.) and 28 mg/kg/d (dermal) after in utero exposure during foetal development.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene glycol

Lanolin

Sorbitan sesquioleate

Hard paraffin

White soft paraffin

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

15 months

After first opening: 8 weeks

6.4 Special Precautions For Storage

Do not store above 25°C.

Do not freeze.

Keep the tube tightly closed.

6.5 Nature And Contents Of Container

30 g

Aluminium tubes with white polyethylene non-piercing screw caps

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

ProStrakan Limited

Galabank Business Park

Galashiels

TD1 1QH

UK

8. Marketing Authorisation Number(S)

PL 16508/0037

9. Date Of First Authorisation/Renewal Of The Authorisation

28/08/2009

10. Date Of Revision Of The Text

28/08/2009

Isopto Carbachol

Generic Name: carbachol ophthalmic (KAR ba kall)

Brand Names: Carbachol Ophthalmic, Carboptic, Isopto Carbachol, Miostat

What is Isopto Carbachol (carbachol ophthalmic)?

Carbachol ophthalmic reduces the pressure in the eye by increasing the amount of fluid that drains from the eye. Carbachol ophthalmic also causes the pupil to become smaller and reduces its response to light or dark conditions.

Carbachol ophthalmic is used to treat glaucoma by lowering the pressure inside the eye.

Carbachol ophthalmic may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Isopto Carbachol (carbachol ophthalmic)?

Contact your doctor immediately if you notice any decrease in vision or an increase in "floaters" in your visual field. Rarely, carbachol ophthalmic may cause retinal detachment. Retinal detachment can lead to blind spots, floaters in your visual field, and even blindness. Your doctor will want to check your retina before you use this medicine to determine if you have an increased risk of retinal detachment. Do not touch the dropper to any surface, including the eyes or hands. The dropper is sterile. If it becomes contaminated, it could cause an infection in the eye.

Apply light pressure to the inside corner of the eye (near the nose) after each drop to prevent the fluid from draining down the tear duct.

Use caution when driving, operating machinery, or performing other hazardous activities. Carbachol ophthalmic may cause decreased vision at night. If you experience decreased vision, avoid these activities.

What should I discuss with my healthcare provider before using Isopto Carbachol (carbachol ophthalmic)?

Rarely, carbachol ophthalmic may cause retinal detachment. Tell your doctor if you have any type of retinal disease, if you have had a retinal tear, if you are nearsighted, or if you have had cataract surgery. These conditions may increase the risk of retinal detachment.

Before using this medication, tell your doctor if you have

• 
  

  heart failure,

  
  


• 
  

  high or low blood pressure,

  
  


• 
  

  ever had a heart attack,

  
  


• 
  

  asthma,

  
  


• 
  

  a stomach ulcer or stomach spasms,

  
  


• 
  

  epilepsy,

  
  


• 
  

  hyperthyroidism (an overactive thyroid),

  
  


• 
  

  blockage of your urinary tract or difficulty urinating, or

  
  


• 
  

  Parkinson's disease.

  
  

You may not be able to use carbachol ophthalmic, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Carbachol ophthalmic is in the FDA pregnancy category C. This means that it is not known whether carbachol ophthalmic will be harmful to an unborn baby. Do not use this medication without first talking to your doctor if you are pregnant or could become pregnant during treatment. It is not known whether carbachol passes into breast milk. Do not use carbachol ophthalmic without first talking to your doctor if you are breast-feeding a baby.

How should I use Isopto Carbachol (carbachol ophthalmic)?

Use carbachol ophthalmic eye drops exactly as directed by your doctor. If you do not understand these instructions, ask your doctor, pharmacist, or nurse to explain them to you.

Wash your hands before using the eye drops.

If you wear contact lenses, remove them before applying carbachol ophthalmic. Ask your doctor if contact lenses can be reinserted after application of the medication. Carbachol ophthalmic may contain a preservative (benzalkonium chloride), which may cause discoloration of contact lenses.

To apply the eye drops:

• 
  

  Tilt the head back slightly and pull down on the lower eyelid. Position the dropper above the eye. Look up and away from the dropper. Squeeze out a drop and close the eye. Apply gentle pressure to the inside corner of the eye (near the nose) for about 1 minute to prevent the liquid from draining down the tear duct. If you are using more than 1 drop in the same eye, repeat the process with about 5 minutes between drops. Repeat the process in the other eye if needed.

  
  

Do not touch the dropper to any surface, including the eyes or hands. The dropper is sterile. If it becomes contaminated, it could cause an infection in the eye. Do not use any eye drop that is discolored or has particles in it. Store carbachol ophthalmic at room temperature away from moisture and heat. Keep the bottle properly capped.

What happens if I miss a dose?

Apply the missed dose as soon as you remember. However, if it is almost time for the next regularly scheduled dose, skip the missed dose and apply the next one as directed. Do not use a double dose of this medication.

What happens if I overdose?

Seek emergency medical attention if an overdose is suspected or if the drops have been ingested.

Symptoms of a carbachol ophthalmic overdose may include sweating, nausea, vomiting, diarrhea, watering mouth, and tearing eyes.

What should I avoid while using Isopto Carbachol (carbachol ophthalmic)?

Use caution when driving, operating machinery, or performing other hazardous activities. Carbachol ophthalmic may cause decreased vision at night. If you experience decreased vision, avoid these activities. Do not touch the dropper to any surface, including the eyes or hands. The dropper is sterile. If it becomes contaminated, it could cause an infection in the eye.

If you wear contact lenses, remove them before applying carbachol ophthalmic. Ask your doctor if contact lenses can be reinserted after application of the medication. Carbachol ophthalmic may contain a preservative (benzalkonium chloride), which may cause discoloration of contact lenses.

Do not use other eye medications during treatment with carbachol ophthalmic except under the direction of your doctor.

Isopto Carbachol (carbachol ophthalmic) side effects

Contact your doctor immediately if you notice any decrease in vision or an increase in "floaters" in your visual field. Rarely, carbachol ophthalmic may cause retinal detachment. Retinal detachment can lead to blind spots, floaters in your visual field, and even blindness. Your doctor will want to check your retina before you use this medicine to determine if you have an increased risk of retinal detachment.

Other, less serious side effects may be more likely to occur. Continue to use carbachol ophthalmic and talk to your doctor if you experience

• 
  

  burning, stinging, or tearing eyes;

  
  


• 
  

  decreased vision in poor light;

  
  


• 
  

  headache;

  
  


• 
  

  watering mouth;

  
  


• 
  

  sweating;

  
  


• 
  

  increased urination;

  
  


• 
  

  nausea, vomiting, or diarrhea; or

  
  


• 
  

  dizziness.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Isopto Carbachol (carbachol ophthalmic)?

Before using this medication, tell your doctor if you are using another eye medication, especially if it is a nonsteroidal anti-inflammatory drug (NSAID) such as flurbiprofen (Ocufen), suprofen (Profenal), diclofenac (Voltaren), or ketorolac (Acular).

Do not use other eye medications during treatment with carbachol ophthalmic except under the direction of your doctor.

Drugs other than those listed here may also interact with carbachol ophthalmic. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including vitamins, minerals, and herbal products.

More Isopto Carbachol resources

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

• Isopto Carbachol Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Isopto Carbachol Advanced Consumer (Micromedex) - Includes Dosage Information


• Carbastat Ocular MedFacts Consumer Leaflet (Wolters Kluwer)


• Carbastat Prescribing Information (FDA)


• Miostat Prescribing Information (FDA)

Compare Isopto Carbachol with other medications

• Glaucoma
• Intraocular Hypertension
• Production of Miosis

Where can I get more information?

• Your pharmacist has additional information about carbachol ophthalmic written for health professionals that you may read.

See also: Isopto Carbachol side effects (in more detail)

Exelderm

sulconazole nitrate

Dosage Form: Cream, 1.0%

For topical use only. Not for ophthalmic use.

Exelderm Description

Exelderm (sulconazole nitrate) CREAM, 1.0% is a broad-spectrum antifungal agent intended for topical application. Sulconazole nitrate, the active ingredient in Exelderm CREAM, is an imidazole derivative with in vitro antifungal and antiyeast activity. Its chemical name is (±)-1-[2,4-Dichloro-β-[(p-chlorobenzyl)thio]phenethyl] imidazole mononitrate and it has the following chemical structure:

Sulconazole nitrate is a white to off-white crystalline powder with a molecular weight of 460.77. It is freely soluble in pyridine; slightly soluble in ethanol, acetone, and chloroform; and very slightly soluble in water. It has a melting point of about 130°C.

Exelderm CREAM contains sulconazole nitrate 10 mg/g in an emollient cream base consisting of propylene glycol, stearyl alcohol, isopropyl myristate, cetyl alcohol, polysorbate 60, sorbitan monostearate, glyceryl stearate (and) PEG-100 stearate, ascorbyl palmitate, and purified water, with sodium hydroxide and/or nitric acid added to adjust the pH.

Exelderm - Clinical Pharmacology

Sulconazole nitrate is an imidazole derivative with broad-spectrum antifungal activity that inhibits the growth in vitro of the common pathogenic dermatophytes including Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum and Microsporum canis. It also inhibits (in vitro) the organism responsible for tinea versicolor, Malassezia furfur. Sulconazole nitrate has been shown to be active in vitro against the following microorganisms, although clinical efficacy has not been established: Candida albicans and certain gram positive bacteria.

A modified Draize test showed no allergic contact dermatitis and a phototoxicity study showed no phototoxic or photoallergic reaction to sulconazole nitrate cream. Maximization tests with sulconazole nitrate cream showed no evidence of contact sensitization or irritation.

Indications and Usage for Exelderm

Exelderm (sulconazole nitrate) CREAM, 1.0% is an antifungal agent indicated for the treatment of tinea pedis (athlete’s foot), tinea cruris, and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis,* and for the treatment of tinea versicolor.

*Efficacy for this organism in the organ system was studied in fewer than ten infections.

Contraindications

Exelderm (sulconazole nitrate) CREAM, 1.0% is contraindicated in patients who have a history of hypersensitivity to any of its ingredients.

Precautions

General

Exelderm (sulconazole nitrate) CREAM, 1.0% is for external use only. Avoid contact with the eyes. If irritation develops, the cream should be discontinued and appropriate therapy instituted.

Information for Patients

Patients should be told to use Exelderm CREAM as directed by the physician, to use it externally only, and to avoid contact with the eyes.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to determine carcinogenic potential have not been performed. In vitro studies have shown no mutagenic activity.

Pregnancy (Category C)

There are no adequate and well controlled studies in pregnant women. Sulconazole nitrate should be used during pregnancy only if clearly needed. Sulconazole nitrate has been shown to be embryotoxic in rats when given in doses of 125 times the adult human dose (in mg/kg). The drug was not teratogenic in rats or rabbits at oral doses of 50 mg/kg/day.

Sulconazole nitrate given orally to rats at a dose 125 times the human dose resulted in prolonged gestation and dystocia. Several females died during the prenatal period, most likely due to labor complications.

Nursing Mothers

It is not known whether sulconazole nitrate is excreted in human milk. Caution should be exercised when sulconazole nitrate is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children have not been established.

Geriatric Use

Clinical studies of Exelderm CREAM, 1.0%, did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

Adverse Reactions

There were no systemic effects and only infrequent cutaneous adverse reactions in 1185 patients treated with sulconazole nitrate cream in controlled clinical trials. Approximately 3% of these patients reported itching, 3% burning or stinging, and 1% redness. These complaints did not usually interfere with treatment.

Clinical Studies

In a vehicle-controlled study for the treatment of tinea pedis (moccasin type) due to T. rubrum, after 4-6 weeks of treatment 69% of patients on the active drug and 19% of patients on the drug vehicle had become KOH and culture negative. In addition, 68% of patients on the active drug and 20% of patients on the drug vehicle showed a good or excellent clinical response.

Exelderm Dosage and Administration

A small amount of cream should be gently massaged into the affected and surrounding skin areas once or twice daily, except in tinea pedis, where administration should be twice daily.

Early relief of symptoms is experienced by the majority of patients and clinical improvement may be seen fairly soon after treatment is begun; however, tinea corporis/cruris and tinea versicolor should be treated for 3 weeks and tinea pedis for 4 weeks to reduce the possibility of recurrence.

If significant clinical improvement is not seen after 4 to 6 weeks of treatment, an alternate diagnosis should be considered.

How is Exelderm Supplied

Exelderm (sulconazole nitrate) CREAM, 1.0%:

     15 g tube - NDC 0072-8200-15

     30 g tube - NDC 0072-8200-30

     60 g tube - NDC 0072-8200-60

Avoid excessive heat, above 40°C (104°F).

U.S. Patent No. 4,055,652

Developed by Syntex

Distributed by:

Westwood-Squibb Pharmaceuticals, Inc.

A Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

51-029707-01

Rev April 2006

Exelderm  sulconazole nitrate  cream

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0072-8200 Route of Administration TOPICAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength sulconazole nitrate (sulconazole) Active 10 MILLIGRAM  In 1 GRAM propylene glycol Inactive   stearyl alcohol Inactive   isopropyl myristate Inactive   cetyl alcohol Inactive   polysorbate 60 Inactive   sorbitan monostearate Inactive   glyceryl stearate (and) PEG-100 stearate Inactive   ascorbyl palmitate Inactive   water Inactive   sodium hydroxide and/or nitric acid Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0072-8200-15 1 TUBE In 1 CARTON contains a TUBE 1 15 g (GRAM) In 1 TUBE This package is contained within the CARTON (0072-8200-15) 2 0072-8200-30 1 TUBE In 1 CARTON contains a TUBE 2 30 g (GRAM) In 1 TUBE This package is contained within the CARTON (0072-8200-30) 3 0072-8200-60 1 TUBE In 1 CARTON contains a TUBE 3 60 g (GRAM) In 1 TUBE This package is contained within the CARTON (0072-8200-60)

Revised: 05/2007Bristol-Myers Squibb Company

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Lexiva

Generic Name: Fosamprenavir Calcium
Class: HIV Protease Inhibitors
VA Class: AM800
Chemical Name: C-[(3S)-tetrahydro-3-furanyl] ester [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)-2-(phosphonooxy)propyl] carbamic acid disodium salt
Molecular Formula: C₂₅H₃₄N₃Na₂O₉PS
CAS Number: 226700-80-7

Introduction

Antiretroviral; HIV protease inhibitor (PI).¹

Uses for Lexiva

Treatment of HIV Infection

Treatment of HIV infection in conjunction with other antiretrovirals.¹

Usually used in PI-based regimens that include a PI and 2 nucleoside reverse transcriptase inhibitors (NRTIs).^{1 3 4}

For initial treatment in HIV-infected adults and adolescents who are treatment-naive, some experts state that ritonavir-boosted fosamprenavir (given once or twice daily) is an alternative (not a preferred) PI for use in PI-based regimens in conjunction with 2 NRTIs.³ These experts state that fosamprenavir (without low-dose ritonavir) should be used with caution in PI-based regimens since such regimens may be associated with virologic failure and result in resistance mutations conferring resistance to other PIs (e.g., darunavir).³

When a PI-based regimen is used in children, some experts state that ritonavir-boosted fosamprenavir (given twice daily) in conjunction with 2 NRTIs is an alternative (not a preferred) regimen for initial treatment in treatment-naive children ≥6 years of age.⁴ These experts state that fosamprenavir (without low-dose ritonavir) in conjunction with 2 NRTIs can be considered for initial treatment in treatment-naive children ≥2 years of age in special circumstances when preferred or alternative PI-based regimens cannot be used.⁴

When selecting fosamprenavir for use in multiple-drug regimens, consider that data are insufficient to date to determine whether a regimen that includes ritonavir-boosted fosamprenavir is as effective as a regimen that includes the fixed-combination of lopinavir and ritonavir in adults who previously received PIs and that once-daily ritonavir-boosted fosamprenavir is not recommended in PI-experienced adults or in any pediatric patient.¹

Postexposure Prophylaxis of HIV

Postexposure prophylaxis of HIV infection† in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with a risk for transmission of the virus.¹¹ Used in conjunction with other antiretrovirals.¹¹

Postexposure prophylaxis of HIV infection† in individuals who have had nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.¹⁰ Used in conjunction with other antiretrovirals.¹⁰

Lexiva Dosage and Administration

Administration

Oral Administration

Tablets

Administer orally without regard to meals.¹

Suspension

Administer with food in children.¹ Administer on an empty stomach in adults.¹

If vomiting occurs soon after a dose (within 30 minutes), repeat dose.¹

Shake well prior to each dose.¹

The taste can be improved by refrigerating the suspension.¹

Dosage

Available as fosamprenavir calcium; dosage expressed in terms of fosamprenavir.¹

Must be given in conjunction with other antiretrovirals.¹ If used with both ritonavir and efavirenz, dosage adjustment may be needed depending on frequency of administration.¹ (See Specific Drugs under Interactions.)

Pediatric Patients

Oral suspension is the preferred dosage form for young children because of suitability for providing the calculated dosage.¹

Children ≥2 years of age: Dosage is based on weight.¹ Do not exceed adult dosage.¹

Once-daily regimen (with or without low-dose ritonavir) is not recommended in pediatric patients.¹

Treatment of HIV Infection

Treatment-naive Pediatric Patients

Oral

Children 2–5 years of age (oral suspension): 30 mg/kg twice daily (without ritonavir).¹

Children ≥6 years of age (oral suspension): 30 mg/kg twice daily (without ritonavir).¹ If ritonavir-boosted regimen used, 18 mg/kg twice daily boosted with low-dose ritonavir (3 mg/kg twice daily).¹

Children weighing ≥39 kg (tablets): 700 mg twice daily boosted with low-dose ritonavir (100 mg twice daily).^{1 4}

Children weighing ≥47 kg (tablets): 1.4 g twice daily (without ritonavir).^{1 4}

Treatment-experienced Pediatric Patients

Oral

Children 2–5 years of age: Data are insufficient for dosage recommendations.¹

Children ≥6 years of age (oral suspension): 18 mg/kg twice daily boosted with low-dose ritonavir (3 mg/kg twice daily).¹

Children weighing ≥39 kg (tablets): 700 mg twice daily boosted with low-dose ritonavir (100 mg twice daily).^{1 4}

Adults

Treatment of HIV Infection

Treatment-naive Adults

Oral

1.4 g twice daily (without ritonavir).¹

1.4 g once daily boosted with low-dose ritonavir (100 or 200 mg once daily) or 700 mg twice daily boosted with low-dose ritonavir (100 mg twice daily).¹

PI-experienced Adults

Oral

700 mg twice daily boosted with low-dose ritonavir (100 mg twice daily).¹ A once-daily regimen of ritonavir-boosted fosamprenavir not recommended in treatment-experienced patients.¹

Postexposure Prophylaxis of HIV†

Occupational Exposure†

Oral

1.4 g twice daily (without ritonavir).¹¹ Alternatively, 1.4 g once daily with low-dose ritonavir (200 mg once daily) or 700 mg twice daily with low-dose ritonavir (100 mg twice daily).¹¹

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.¹¹

Nonoccupational Exposure†

Oral

1.4 g twice daily (without ritonavir).¹⁰

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.¹⁰

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Oral

Maximum 1.4 g twice daily (without ritonavir) or 700 mg twice daily boosted with ritonavir (100 mg twice daily).¹ Do not exceed adult dosage.¹

Adults

Treatment of HIV Infection

Treatment-naive Adults

Oral

Maximum 1.4 g once daily boosted with ritonavir (200 mg once daily) or 700 mg twice daily boosted with ritonavir (100 mg twice daily).¹ Higher than recommended dosages of fosamprenavir and/or ritonavir associated with increased serum transaminase concentrations; higher dosages not recommended.¹

PI-experienced Adults

Oral

Maximum 700 mg twice daily boosted with ritonavir (100 mg twice daily).¹ Higher than recommended dosages of fosamprenavir and/or ritonavir associated with increased serum transaminase concentrations; higher dosages not recommended.¹

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh score 5–6): Use with caution.¹ If fosamprenavir (without ritonavir) is used, treatment-naive adults should receive fosamprenavir 700 mg twice daily.¹ If ritonavir-boosted fosamprenavir is used, treatment-naive and treatment-experienced adults should receive fosamprenavir 700 mg twice daily with low-dose ritonavir (100 mg once daily).¹

Moderate hepatic impairment (Child-Pugh score 7–9): Use with caution.¹ If fosamprenavir (without ritonavir) is used, treatment-naive adults should receive fosamprenavir 700 mg twice daily.¹ If ritonavir-boosted fosamprenavir is used, treatment-naive and treatment-experienced adults should receive fosamprenavir 450 mg twice daily with low-dose ritonavir (100 mg once daily).¹

Severe hepatic impairment (Child-Pugh score 10–15): Use with caution.¹ If fosamprenavir (without ritonavir) is used, treatment-naive adults should receive fosamprenavir 350 mg twice daily.¹ If ritonavir-boosted fosamprenavir is used, treatment-naive and treatment-experienced adults should receive fosamprenavir 300 mg twice daily with low-dose ritonavir (100 mg once daily).¹

Renal Impairment

Dosage adjustment not necessary.³

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Lexiva

Contraindications

• 
  

  Known hypersensitivity to fosamprenavir, amprenavir (no longer commercially available in the US), or any ingredient in the formulation.¹

  
  


• 
  

  Concomitant use with drugs highly dependent on CYP3A4 for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (i.e., rifampin, ergot alkaloids, cisapride, St. John’s wort, lovastatin, simvastatin, pimozide, delavirdine, midazolam, triazolam).¹ (See Specific Drugs under Interactions.)

  
  


• 
  

  Concomitant use of a ritonavir-boosted fosamprenavir regimen and flecainide or propafenone.¹ (See Antiarrhythmic Agents under Interactions.)

  
  

Warnings/Precautions

Sensitivity Reactions

Dermatologic and Hypersensitivity Reactions

Rash (usually maculopapular and of mild to moderate intensity, with or without pruritus) reported.¹ Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, reported rarely.¹

Discontinue if severe or life-threatening rash or moderate rash accompanied by systemic symptoms occurs.¹

Sulfonamide Sensitivity

Because fosamprenavir contains a sulfonamide moiety, use with caution in patients with known sulfonamide allergy.¹

Potential for cross-sensitivity between sulfonamide drugs and fosamprenavir unknown.¹

Interactions

When a ritonavir-boosted fosamprenavir regimen is used, the usual cautions, precautions, and contrainfdications associated with ritonavir should be considered.¹

Serious and/or life-threatening drug interactions or loss of virologic effect can occur with some drugs.¹ (See Contraindications and Specific Drugs under Interactions.)

Hepatic Effects

Patients with coexisting hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or marked elevations in transaminase concentrations prior to fosamprenavir therapy may be at increased risk for developing transaminase elevations.¹

Perform appropriate laboratory tests to evaluate hepatic function prior to initiating fosamprenavir therapy and monitor patients closely during treatment.¹ (See Hepatic Impairment under Cautions.)

Use of fosamprenavir with ritonavir at higher than recommended dosages may result in elevated transaminase concentrations.¹

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of PIs; diabetic ketoacidosis has occurred.¹

Monitor blood glucose and initiate or adjust dosage of insulin or oral hypoglycemic agents as needed.¹

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]);¹ this may necessitate further evaluation and treatment.¹

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance.¹ Evaluate patients for physical signs of fat redistribution.¹⁹

Lipid Effects

Increases in triglyceride and cholesterol concentrations have occurred with ritonavir-boosted fosamprenavir.^{1 19 21} HIV infection itself is associated with lipid disorders.¹⁹

Determine serum triglyceride and cholesterol concentrations prior to initiating fosamprenavir and periodically monitor during therapy; manage lipid disorders as clinically appropriate.^{1 19} (See HMG-CoA Reductase Inhibitors under Interactions.)

Hematologic Effects

Neutropenia has been reported with fosamprenavir;¹ acute hemolytic anemia has been reported in at least one patient who received amprenavir (no longer commercially available in the US).¹

Hemophilia A and B

Spontaneous bleeding reported with PIs;¹ causal relationship not established.¹

Use with caution in patients with hemophilia A or B.^{1 3} Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.¹

Nephrolithiasis

Nephrolithiasis reported in postmarketing surveillance.^{1 19} If signs or symptoms of nephrolithiasis occur, consider temporarily interrupting or discontinuing fosamprenavir.^{1 19}

HIV Resistance

Possible amprenavir resistance in patients treated with fosamprenavir.¹ The possible effect of fosamprenavir therapy on subsequent therapy with other PIs unknown.¹

Cardiovascular Effects

Postmarketing reports of myocardial infarction in patients receiving fosamprenavir.¹ Possible association between cumulative exposure to fosamprenavir/amprenavir and increased risk of myocardial infarction.¹⁹ Higher relative risk of myocardial infarction reported with PIs compared with other antiretroviral drug classes, possibly due to ability of PIs to elevate serum lipid concentrations.^{19 20} HIV infection itself is associated with ischemic heart disease.¹⁹

Monitor modifiable risk factors for cardiovascular disease (e.g., hypertension, diabetes, smoking) and manage as clinically appropriate.¹⁹ Individualize treatment, carefully considering risks and benefits of continued treatment.¹⁹

Specific Populations

Pregnancy

Category C.¹

Antiretroviral Pregnancy Registry at 800-258-4263.¹

Some experts state safety and pharmacokinetic data insufficient to recommend routine use of fosamprenavir in pregnant women, but ritonavir-boosted fosamprenavir may be considered if other antiretroviral agents are not tolerated.¹²

Lactation

Distributed into milk in rats;¹ not known whether distributed into human milk.¹

Instruct HIV-infected women not to breast-feed^{1 12} because of risk of HIV transmission and risk of adverse effects in the infant.^{1 2}

Pediatric Use

Safety and efficacy not established in children <2 years of age.¹

Once-daily regimen not recommended in pediatric patients.¹

Adverse effects in children 2–18 years of age similar to those reported in adults; vomiting reported more frequently in pediatric patients than in adults.¹

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently from younger adults.¹

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Hepatic Impairment

Clearance decreased.¹

Use with caution; assess hepatic function prior to and periodically during therapy.¹

Dosage adjustments necessary in patients with hepatic impairment (Child-Pugh score 5–15).¹ (See Hepatic Impairment under Dosage and Administration.)

Increased risk for further elevations in hepatic enzyme concentrations in patients with chronic HBV or HCV infection and those with marked increases in AST or ALT concentrations prior to fosamprenavir therapy.¹

Common Adverse Effects

Diarrhea, nausea, vomiting, headache, rash.¹

Interactions for Lexiva

Amprenavir (active metabolite of fosamprenavir) is metabolized by CYP3A4.¹

Amprenavir inhibits CYP3A4 and also may induce CYP3A4.¹

Amprenavir does not inhibit CYP2D6, 1A2, 2C9, 2C19, or P2E1¹ or uridine glucuronosyltransferase (UDPGT).¹

Some interaction studies have been performed using fosamprenavir.¹ These studies may not predict magnitude of interaction with ritonavir-boosted fosamprenavir.¹

Since fosamprenavir is metabolized to amprenavir, interactions reported with amprenavir (no longer commercially available in the US) also apply to fosamprenavir.¹

When fosamprenavir is used with low-dose ritonavir, consider interactions reported with low-dose ritonavir.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors or substrates of CYP3A4 with possible alteration in metabolism of amprenavir and/or the other drug.¹

Specific Drugs

Drug	Interaction	Comments
Abacavir	Studies using amprenavir indicate pharmacokinetic interaction unlikely1 In vitro evidence of synergistic antiretroviral effects1
Alfuzosin	Potential for increased alfuzosin concentrations that could result in hypotension1	Concomitant use with fosamprenavir (with or without low-dose ritonavir) is contraindicated1
Antacids	Decreased amprenavir concentrations and AUC1	Not considered clinically important; manufacturer states there are no restrictions for concomitant use of fosamprenavir and antacids2
Antiarrhythmic agents (amiodarone, flecainide, systemic lidocaine, propafenone, quinidine)	Possible increased antiarrhythmic agent concentrations1 Potential for serious or life-threatening effects (e.g., cardiac arrhythmias) if ritonavir-boosted fosamprenavir used in patients receiving flecainide or propafenone1 Potential for serious or life-threatening effects (e.g., cardiac arrhythmias) if fosamprenavir used in conjunction with amiodarone, systemic lidocaine, or quinidine1	In patients receiving ritonavir-boosted fosamprenavir, concomitant use with flecainide or propafenone contraindicated1 Caution if fosamprenavir used concomitantly with amiodarone, systemic lidocaine, or quinidine; antiarrhythmic concentration monitoring recommended1
Anticoagulants, oral	Warfarin concentrations may be affected1	Monitor INR1
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Fosamprenavir: Possible decreased amprenavir concentrations when used with carbamazepine, phenobarbital, or phenytoin;1 possible decreased antiretroviral efficacy1 Ritonavir-boosted fosamprenavir and phenytoin: Increased concentrations of amprenavir and decreased concentrations of phenytoin1	Fosamprenavir (without low-dose ritonavir): Use concomitantly with caution1 Ritonavir-boosted fosamprenavir: Monitor phenytoin concentrations; increase phenytoin dosage if indicated; no dosage adjustment recommended for ritonavir-boosted fosamprenavir 1
Antidepressants, tricyclics	Possible increased concentrations of tricyclic antidepressants (amitriptyline, imipramine) 1	Monitor tricyclic antidepressant concentrations1
Antifungals, azoles (itraconazole, ketoconazole, voriconazole)	Itraconazole: Possible increased antifungal and amprenavir concentrations1 3 Ketoconazole: Possible increased ketoconazole concentrations with fosamprenavir (with or without low-dose ritonavir)1 3 Voriconazole: Although specific data not available on interaction with ritonavir-boosted fosamprenavir, studies using low-dose ritonavir and voriconazole indicate decreased voriconazole concentrations;3 9 in addition, fosamprenavir (without ritonavir) possibly may result in increased concentrations of both drugs3	Itraconazole: In patients receiving fosamprenavir (with or without ritonavir), consider monitoring itraconazole concentrations to guide dosage adjustments; in those receiving fosamprenavir (without ritonavir), may need to reduce antifungal dosage in those receiving >400 mg of itraconazole daily;1 3 in those receiving ritonavir-boosted fosamprenavir, itraconazole dosage >200 mg daily not recommended unless plasma concentrations are monitored1 3 Ketoconazole: In patients receiving fosamprenavir (without ritonavir), may need to reduce antifungal dosage in those receiving >400 mg of ketoconazole daily;1 in those receiving ritonavir-boosted fosamprenavir, use caution and ketoconazole dosage >200 mg daily not recommended1 Voriconazole: Concomitant ritonavir-boosted fosamprenavir not recommended unless potential benefits outweigh risks; consider monitoring voriconazole plasma concentrations;3 9 if fosamprenavir (without ritonavir) is used, monitor frequently for toxicity3 9
Antimycobacterials (rifabutin, rifampin, rifapentine)	Rifabutin: 150 mg every other day with ritonavir-boosted fosamprenavir results in increased amprenavir concentrations and increased rifabutin metabolite concentrations compared with rifabutin 300 mg daily alone1 Rifampin: Studies using amprenavir indicate decreased amprenavir concentrations;1 possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1	Rifabutin: If fosamprenavir (without ritonavir) used with rifabutin, reduce rifabutin dosage by at least 50%1 (150 mg once daily or 300 mg 3 times weekly has been suggested);3 if ritonavir-boosted fosamprenavir used with rifabutin, reduce rifabutin dosage by at least 75% (maximum dosage of 150 mg once every other day or 3 times weekly);1 3 monitor for neutropenia by performing CBCs weekly and as clinically indicated1 Rifampin: Concomitant use contraindicated1 Rifapentine: Concomitant use not recommended3
Atazanavir	Decreased atazanavir concentrations; no change in amprenavir concentrations1	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 3
Benzodiazepines (alprazolam, clorazepate, diazepam, flurazepam, midazolam, triazolam)	Midazolam or triazolam: Possible increased concentrations of midazolam or triazolam; potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression)1 Other benzodiazepines: Possible increased concentrations of alprazolam, clorazepate, diazepam, flurazepam1	Midazolam or triazolam: Manufacturer of fosamprenavir states that concomitant use is contraindicated;1 some experts state a single parenteral dose of midazolam can be used with caution in a monitored situation for procedural sedation3 Other benzodiazepines: Clinical importance of pharmacokinetic interaction unknown; a decrease in benzodiazepine dosage may be needed1
Bosentan	Increased bosentan concentrations1	In patients already receiving fosamprenavir (with or without low-dose ritonavir) for ≥10 days, initiate bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1 3 In patients already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating fosamprenavir (with or without low-dose ritonavir); after ≥10 days of fosamprenavir, resume bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1 3
Calcium-channel blocking agents (diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine)	Possible increased concentrations of calcium-channel blocking agent1	Use concomitantly with caution; clinical monitoring recommended1
Cisapride	Possible increased cisapride concentrations; potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1
Clarithromycin	Studies using amprenavir indicate increased amprenavir concentrations and AUC1	Not considered clinically important;2 dosage adjustment not needed3
Colchicine	Increased colchicine concentrations1	Patients with renal or hepatic impairment: Avoid concomitant use of colchicine and ritonavir-boosted fosamprenavir1 Colchicine for treatment of gout flares: In those receiving ritonavir-boosted fosamprenavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later; in those receiving fosamprenavir (without ritonavir), use initial colchicine dose of 1.2 mg and repeat dose no earlier than 3 days later1 Colchicine for prophylaxis of gout flares: In those receiving ritonavir-boosted fosamprenavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 once daily;1 in those receiving fosamprenavir (without ritonavir), decrease colchicine dosage to 0.3 mg twice daily or 0.6 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once daily in those originally receiving 0.6 mg once daily1 Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir-boosted fosamprenavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily);1 in those receiving fosamprenavir (without ritonavir), use maximum colchicine dosage of 1.2 mg daily (may be given as 0.6 mg twice daily)1
Corticosteroids (dexamethasone, fluticasone)	Fluticasone nasal spray/oral inhalation: Increased fluticasone concentrations with fosamprenavir (with or without low-dose ritonavir) resulting in decreased cortisol concentrations1 Dexamethasone: Possible decreased amprenavir concentrations; possible decreased antiretroviral efficacy1	Fluticasone nasal spray/oral inhalation: Consider alternative in patients receiving fosamprenavir (without ritonavir), especially when long-term corticosteroid therapy is anticipated; concomitant use with ritonavir-boosted fosamprenavir not recommended unless potential benefits outweigh risk of systemic corticosteroid adverse effects1 Dexamethasone: Use concomitantly with caution1
Darunavir	Data not available regarding concomitant use of darunavir and fosamprenavir (with or without low-dose ritonavir)3
Delavirdine	Studies using amprenavir indicate possible increased amprenavir concentrations and AUC and possible decreased delavirdine plasma concentrations and AUC;1 possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1 In vitro evidence of synergistic antiretroviral effects1	Concomitant use contraindicated1
Didanosine	In vitro evidence of synergistic antiretroviral effects1
Efavirenz	Substantially decreased amprenavir concentrations if used with fosamprenavir;1 additional pharmacokinetic interactions if ritonavir-boosted fosamprenavir used1 In vitro evidence of synergistic antiretroviral effects1	If fosamprenavir used with efavirenz, boosting with ritonavir required 1 2 3 When efavirenz used with ritonavir-boosted fosamprenavir, fosamprenavir 1.4 g once daily with ritonavir 300 mg once daily or fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily recommended1 3
Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)	Possible increased concentrations of ergot alkaloids and potential for serious and/or life-threatening effects such as ergot toxicity (peripheral vasospasm and ischemia of the extremities and other tissues)1	Concomitant use contraindicated1 If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving fosamprenavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible12
Estrogens or Progestins	Hormonal contraceptive containing ethinyl estradiol 35 mcg with norethindrone 0.5 mg per tablet: Decreased ethinyl estradiol and norethindrone concentrations with ritonavir-boosted fosamprenavir; clinically important increase in serum transaminase concentrations1 Hormonal contraceptives: Possible loss of virologic response if used with fosamprenavir (without ritonavir)1 Hormone replacement therapy: Possible increase in serum transaminase concentrations with ritonavir-boosted fosamprenavir1	Hormonal contraceptives: Concomitant use not recommended;3 use alternative nonhormonal (e.g., barrier) contraceptives1 3
Etravirine	Fosamprenavir or ritonavir-boosted fosamprenavir: Substantially increased amprenavir concentrations17	Do not administer concomitantly;3 17 appropriate dosages for concomitant use with respect to safety and efficacy not established3 17
Histamine H2-receptor antagonists (cimetidine, famotidine, nizatidine, ranitidine)	Decreased amprenavir plasma concentrations and AUC;1 possible decreased antiretroviral efficacy1	Use concomitantly with caution;1 administer at different times;3 consider using ritonavir-boosted fosamprenavir3
HMG-CoA reductase inhibitors (statins)	Possible decreased clearance and increased concentrations of some HMG-CoA reductase inhibitors (e.g., atorvastatin, rosuvastatin) with potential for increased risk of myopathy (including rhabdomyolysis)1	Lovastatin or simvastatin: Concomitant use with fosamprenavir contraindicated1 Atorvastatin or rosuvastatin: Use lowest possible dosage of the HMG-CoA reductase inhibitor with careful monitoring1 Consider using HMG-CoA reductase inhibitors with low potential for interaction (e.g., fluvastatin, pravastatin)1
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Potential for increased concentrations of cyclosporine, sirolimus, or tacrolimus1	Monitor concentrations of the immunosuppressive agent1
Indinavir	Studies using amprenavir indicate possible increased amprenavir plasma concentrations and AUC and decreased indinavir concentrations;1 concomitant use of ritonavir-boosted fosamprenavir not evaluated1 In vitro evidence of additive antiretroviral effects1	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 3
Lamivudine	Studies using amprenavir indicate no evidence of pharmacokinetic interaction1 In vitro evidence of synergistic antiretroviral effects1
Lopinavir	Fosamprenavir: Decreased amprenavir concentrations; no change in lopinavir concentrations 1 Ritonavir-boosted fosamprenavir: Decreased amprenavir concentrations; altered lopinavir concentrations1 Increased incidence of adverse effects reported1 In vitro evidence of additive antiretroviral effects1	Appropriate dosages for concomitant use with respect to safety and efficacy not established;1 3 concomitant use not recommended3
Maraviroc	Possible increased concentrations of maraviroc3	Recommended dosage of maraviroc is 150 mg twice daily3
Methadone	Decreased methadone concentrations1	Not considered clinically important; monitor for symptoms of opiate withdrawal and adjust methadone dosage if needed1 3
Nelfinavir	Studies using amprenavir indicate possible alterations in amprenavir and nelfinavir pharmacokinetics;1 concomitant use of ritonavir-boosted fosamprenavir and nelfinavir not evaluated1 In vitro evidence of additive antiretroviral effects1	Appropriate dosages for concomitant use with respect to safety and efficacy not established1
Nevirapine	Decreased amprenavir concentrations and increased nevirapine concentrations with fosamprenavir (without ritonavir); clinically important interaction unlikely with ritonavir-boosted fosamprenavir1 In vitro evidence of additive antiretroviral effects1	Concomitant use of fosamprenavir (without ritonavir) with nevirapine not recommended1 Dosage adjustment not needed when ritonavir-boosted fosamprenavir is given twice daily with nevirapine; concomitant use with ritonavir-boosted fosamprenavir given once daily not studied1
Paroxetine	Decreased paroxetine concentrations with ritonavir-boosted fosamprenavir1	Monitor closely for antidepressant response;3 adjust paroxetine dosage based on clinical effects1 3
Pimozide	Possible increased pimozide concentrations;1 potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1
Proton-pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)	Esomeprazole: When used with fosamprenavir (without ritonavir), no change in amprenavir concentrations or AUC, and increased esomeprazole AUC;1 when used with ritonavir-boosted fosamprenavir, clinically important pharmacokinetic interaction unlikely1	Can be administered at the same time as proton-pump inhibitors with no change in plasma amprenavir concentrations1
Ritonavir	Increased plasma concentrations and AUC of amprenavir1 3 Concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted fosamprenavir);1 increased potential for drug interactions since ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D61 In vitro evidence of additive antiretroviral effects1	When ritonavir-boosted fosamprenavir is used in a once-daily regimen, recommended dosage is fosamprenavir 1.4 g once daily with ritonavir 100 or 200 mg once daily; when used in a twice-daily regimen, recommended dosage is fosamprenavir 700 mg twice with ritonavir 100 mg twice daily1 3 Once-daily regimen of ritonavir-boosted fosamprenavir not recommended in PI-experienced patients1
St. John’s wort (Hypericum perforatum)	Possible decreased amprenavir concentrations;1 possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1	Concomitant use contraindicated1
Saquinavir	Decreased amprenavir concentrations1 In vitro evidence of synergistic antiretroviral effects1	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 3
Sildenafil	Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1	Sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH): Concomitant use with fosamprenavir (with or without low-dose ritonavir) is contraindicated;1 3 fosamprenavir manufacturer states that a safe and effective dose for concomitant use not established1 Sildenafil for treatment of erectile dysfunction: If used concomitantly with fosamprenavir (with or without low-dose ritonavir), use reduced sildenafil dosage (25 mg repeated no more frequently than once every 48 hours) and monitor closely for adverse sildenafil effects1 3
Stavudine	In vitro evidence of synergistic antiretroviral effects1
Tadalafil	Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1 3	If tadalafil (Adcirca) is initiated for treatment of PAH in patients already receiving fosamprenavir (with or without low-dose ritonavir) for ≥1 week, use an initial tadalafil dosage of 20 mg once daily and increase dosage to 40 mg once daily based on individual tolerability1 Avoid use of tadalafil (Adcirca) for treatment of PAH during initiation of fosamprenavir (with or