Peridol

Generic Name: haloperidol (Oral route)

hal-oh-PER-i-dol

Oral route(Tablet)

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Although the causes of death in clinical trials were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that antipsychotic drugs may increase mortality. It is unclear from these studies to what extent the mortality findings may be attributed to the antipsychotic drug as opposed to patient characteristics. Haloperidol is not approved for the treatment of patients with dementia-related psychosis .

Commonly used brand name(s)

In the U.S.

• Haldol

In Canada

• Alti-Haloperidol


• Apo-Haloperidol


• Novo-Peridol


• Peridol


• Pms-Haloperidol


• Ratio-Haloperidol

Available Dosage Forms:

• Tablet


• Solution

Therapeutic Class: Antipsychotic

Pharmacologic Class: Dopamine Antagonist

Chemical Class: Butyrophenone

Uses For Peridol

Haloperidol is used to treat nervous, emotional, and mental conditions (e.g., schizophrenia). It is also used to control the symptoms of Tourette's disorder. This medicine should not be used to treat behavior problems in older adult patients who have dementia.

Haloperidol is also used to treat severe behavioral problems (e.g., aggressive, impulsive behavior) or hyperactivity in children who have already been treated with psychotherapy or other medicines that did not work well.

This medicine is available only with your doctor's prescription.

Before Using Peridol

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

Appropriate studies have not been performed on the relationship of age to the effects of haloperidol in children younger than 3 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of haloperidol in the elderly. However, elderly women are more likely to have a side effect called tardive dyskinesia, and elderly patients are more likely to have age-related heart problems, which may require an adjustment in the dose for patients receiving haloperidol.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

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.

• Bepridil


• Cisapride


• Dronedarone


• Levomethadyl


• Mesoridazine


• Metoclopramide


• Pimozide


• Sparfloxacin


• Terfenadine


• Thioridazine

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.

• Acecainide


• Ajmaline


• Alfuzosin


• Amiodarone


• Amisulpride


• Amitriptyline


• Amoxapine


• Apomorphine


• Aprindine


• Arsenic Trioxide


• Asenapine


• Astemizole


• Azimilide


• Azithromycin


• Bretylium


• Chloral Hydrate


• Chloroquine


• Chlorpromazine


• Ciprofloxacin


• Citalopram


• Clarithromycin


• Clomipramine


• Clozapine


• Crizotinib


• Dalfopristin


• Dasatinib


• Desipramine


• Dibenzepin


• Disopyramide


• Dofetilide


• Dolasetron


• Doxepin


• Droperidol


• Encainide


• Enflurane


• Erythromycin


• Flecainide


• Fluconazole


• Fluoxetine


• Foscarnet


• Gatifloxacin


• Gemifloxacin


• Granisetron


• Halofantrine


• Halothane


• Hydromorphone


• Hydroquinidine


• Ibutilide


• Imipramine


• Isoflurane


• Isradipine


• Ketoconazole


• Lapatinib


• Levofloxacin


• Lidoflazine


• Lithium


• Lopinavir


• Lorcainide


• Lumefantrine


• Mefloquine


• Methadone


• Milnacipran


• Moxifloxacin


• Nilotinib


• Norfloxacin


• Nortriptyline


• Octreotide


• Ofloxacin


• Ondansetron


• Paliperidone


• Paroxetine


• Pazopanib


• Pentamidine


• Perflutren Lipid Microsphere


• Pirmenol


• Posaconazole


• Prajmaline


• Probucol


• Procainamide


• Prochlorperazine


• Promethazine


• Propafenone


• Propranolol


• Protriptyline


• Quetiapine


• Quinidine


• Quinine


• Quinupristin


• Ranolazine


• Risperidone


• Salmeterol


• Saquinavir


• Sematilide


• Sertindole


• Sodium Phosphate


• Sodium Phosphate, Dibasic


• Sodium Phosphate, Monobasic


• Solifenacin


• Sorafenib


• Sotalol


• Spiramycin


• Sulfamethoxazole


• Sultopride


• Sunitinib


• Tedisamil


• Telavancin


• Telithromycin


• Tetrabenazine


• Toremifene


• Tramadol


• Trazodone


• Trifluoperazine


• Trimethoprim


• Trimipramine


• Vandetanib


• Vardenafil


• Vasopressin


• Vemurafenib


• Venlafaxine


• Voriconazole


• Ziprasidone


• Zolmitriptan


• Zotepine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Benztropine


• Betel Nut


• Bupropion


• Buspirone


• Carbamazepine


• Dextromethorphan


• Fluvoxamine


• Methyldopa


• Nefazodone


• Olanzapine


• Procyclidine


• Rifampin


• Rifapentine


• Tacrine


• Trihexyphenidyl

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:

• Breast cancer, history of or


• Chest pain or


• Heart or blood vessel disease, severe or


• Hyperprolactinemia (high prolactin in the blood) or


• Hypotension (low blood pressure) or


• Mania or


• Neuroleptic malignant syndrome, history of or


• Seizures or epilepsy, history of—Use with caution. May make these conditions worse.

• Central nervous system depression, severe or


• Coma or


• Dementia in elderly or


• Parkinson's disease—Should not be used in patients with these conditions.

• Heart rhythm problems (e.g., familial long QT-syndrome), history of or


• Hypokalemia (low potassium in the blood) or


• Hypomagnesemia (low magnesium in the blood) or


• Hypothyroidism (underactive thyroid) or


• Thyrotoxicosis (overactive thyroid)—May increase risk for more serious side effects.

Proper Use of haloperidol

This section provides information on the proper use of a number of products that contain haloperidol. It may not be specific to Peridol. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This is particularly important for elderly patients, since they may react very strongly to this medicine.

For patients taking the liquid form of this medicine:

• This medicine is to be taken by mouth and it comes in a dropper bottle. Each dose is to be measured with the specially marked dropper provided with your bottle. Do not use other droppers since they may not deliver the correct amount of medicine.


• This medicine should be mixed with water or a beverage, such as orange juice, apple juice, tomato juice, or cola, and taken immediately after mixing.

Continue taking this medicine for the full time of treatment. Sometimes haloperidol must be taken for several days to several weeks before its full effect is reached.

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.

• For oral dosage forms (solution and tablets):
  
  • For nervous, emotional, or mental conditions:
    
    • Adults and teenagers—At first, 0.5 to 5 milligrams (mg) two or three times a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 100 mg per day.
    
    
    • Older adults—At first, 0.5 to 2 milligrams (mg) two or three times a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 100 mg per day.
    
    
    • Children 3 to 12 years of age or weighing 15 to 40 kilograms (kg)—Dose is based on body weight and must be determined by your doctor. The usual dose is 50 to 150 micrograms per kg per day, given in divided doses two or three times a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 6 mg per day.
    
    
    • Children below 3 years of age—Use and dose must be determined by the doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Peridol

Your doctor should check your progress at regular visits, especially during the first few months of treatment with this medicine. The amount of haloperidol you take may be changed to meet the needs of your condition and to prevent side effects.

Do not stop taking this medicine without checking first with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping completely. This will allow your body time to adjust and help avoid a worsening of your medical condition.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using this medicine.

This medicine may cause some people to become dizzy, drowsy, or less alert than they are normally, especially as the amount of medicine is increased. Even if you take haloperidol at bedtime, you may feel drowsy or less alert on arising. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. Getting up slowly may help. If this problem continues or gets worse, check with your doctor.

This medicine will often make you sweat less, causing your body temperature to increase. Use extra care not to become overheated during exercise or hot weather while you are taking this medicine, since overheating may result in heat stroke. Also, hot baths or saunas may make you feel dizzy or faint while you are using this medicine.

Haloperidol may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight, even for brief periods of time, may cause a skin rash, itching, redness or other discoloration of the skin, or a severe sunburn. When you begin taking this medicine:

• Stay out of direct sunlight, especially between the hours of 10:00 a.m. and 3:00 p.m., if possible.


• Wear protective clothing, including a hat or sunglasses.


• Apply a sun block product that has a skin protection factor (SPF) of at least 15. Some patients may require a product with a higher SPF number, especially if they have a fair complexion. If you have any questions about this, check with your doctor.


• Apply a sun block lipstick that has an SPF of at least 15 to protect your lips.


• Do not use a sunlamp or tanning bed or booth.

If you have a severe reaction from the sun, check with your doctor.

Haloperidol may cause dry mouth. For temporary relief, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if your mouth continues to feel dry for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

Contact your doctor as soon as possible if you have chest pain or discomfort, a fast heartbeat, trouble breathing, or fever and chills. These can be symptoms of a very serious problem with your heart.

This medicine may cause tardive dyskinesia (a movement disorder). Check with your doctor right away if you have any of the following symptoms while taking this medicine: lip smacking or puckering, puffing of the cheeks, rapid or worm-like movements of the tongue, uncontrolled chewing movements, or uncontrolled movements of the arms and legs.

Stop taking this medicine and check with your doctor right away if you have any of the following symptoms while using this medicine: convulsions (seizures); difficulty with breathing; a fast heartbeat; a high fever; high or low blood pressure; increased sweating; loss of bladder control; severe muscle stiffness; unusually pale skin; or tiredness. These could be symptoms of a serious condition called neuroleptic malignant syndrome (NMS).

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Peridol Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

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

More common

• Difficulty with speaking or swallowing


• inability to move the eyes


• loss of balance control


• mask-like face


• muscle spasms, especially of the neck and back


• restlessness or need to keep moving (severe)


• shuffling walk


• stiffness of the arms and legs


• trembling and shaking of the fingers and hands


• twisting movements of the body


• weakness of the arms and legs

Less common

• Decreased thirst


• difficulty in urination


• dizziness, lightheadedness, or fainting


• hallucinations (seeing or hearing things that are not there)


• lip smacking or puckering


• puffing of the cheeks


• rapid or worm-like movements of the tongue


• skin rash


• uncontrolled chewing movements


• uncontrolled movements of the arms and legs

Rare

• Confusion


• convulsions (seizures)


• difficult or fast breathing


• fast heartbeat or irregular pulse


• fever (high)


• high or low blood pressure


• hot, dry skin, or lack of sweating


• increased blinking or spasms of the eyelid


• increased sweating


• loss of bladder control


• muscle stiffness (severe)


• muscle weakness


• sore throat and fever


• uncontrolled twisting movements of the neck, trunk, arms, or legs


• unusual bleeding or bruising


• unusual facial expressions or body positions


• unusual tiredness or weakness


• unusually pale skin


• yellow eyes or skin

Incidence not known

• Continuing nausea or vomiting


• increase in the frequency of seizures


• loss of appetite


• swelling of the face


• tiredness and weakness

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Difficulty with breathing (severe)


• dizziness (severe)


• drowsiness (severe)


• muscle trembling, jerking, stiffness, or uncontrolled movements (severe)


• unusual tiredness or weakness (severe)

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

• Blurred vision


• changes in menstrual period


• constipation


• dryness of the mouth


• swelling or pain in the breasts (in females)


• unusual secretion of milk


• weight gain

Less common

• Decreased sexual ability


• drowsiness


• increased sensitivity of the skin to sun (skin rash, itching, redness or other discoloration of skin, or severe sunburn)


• nausea or vomiting

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: Peridol side effects (in more detail)

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More Peridol resources

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

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Timodine (Alliance Pharmaceuticals)

1. Name Of The Medicinal Product

Timodine Cream.

2. Qualitative And Quantitative Composition

Active ingredient	%w/w
Nystatin*	3.00
Dimeticone 350	10.00
Hydrocortisone**	0.50
Benzalkonium chloride solution (equivalent to benzalkonium chloride 0.10g)	0.20

*An overage of 15% is added at manufacture. The 3% w/w is approximate only to achieve an activity of nystatin in the final formulation of 100,000 IU/g.

**An overage of 8% is added at manufacture.

Excipients	%w/w
Cetostearyl alcohol	1.51
Butylated hydroxyanisole compound (containing butylated hydroxyanisole (E320) 20%, propyl gallate 10% and citric acid 10%)	0.40
Methyl hydroxybenzoate (E218)	0.10
Propyl hydroxybenzoate (E216)	0.10
Sorbic acid	0.10

For a full list of excipients, see Section 6.1.

3. Pharmaceutical Form

Cream.

A pale yellow cream.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of dermatoses, including intertrigo, eczema, seborrhoeic dermatitis, “Housewife's” eczema, and pruritis ani et vulvae, in which infection with Candida albicans is a factor. For the treatment of severe nappy rash in which infection with C. albicans is a factor.

4.2 Posology And Method Of Administration

For topical application to the skin.

Adults (including the elderly) and children.

Dermatoses: Sufficient Timodine Cream should be applied to cover the lesion in a thin layer. It should then be massaged into the skin until the cream disappears.

The treatment should be repeated three times a day until the lesion has healed.

There is no indication that dosage need be modified for the elderly.

Nappy rash: After removal of the soiled nappy, the affected area should be cleaned and dried, and a thin layer of Timodine Cream applied. The treatment should be repeated after every nappy change. In infants long-term continuous topical steroid therapy should be avoided since this can lead to adrenal suppression even without occlusion. A course of treatment should not normally exceed seven days.

4.3 Contraindications

Timodine Cream is contra-indicated for use in the following conditions:

• rosacea

• perioral dermatitis

• untreated bacterial, fungal or viral skin infections

• ulcerated skin

Known hypersensitivity to nystatin, dimeticone 350, hydrocortisone or benzalkonium chloride solution, or to any of the excipients (see Section 6.1 'List of excipients')

4.4 Special Warnings And Precautions For Use

In order to minimise the side effects of a topical corticosteroid, it is important to apply it thinly to the affected areas only. Topical corticosteroids should not be applied with an occlusive dressing to large areas of the body. Absorption is greatest on thin/raw skin, intertriginous areas, and under occlusion. Skin thinning is more likely if corticosteroids are applied under occlusion.

Absorption of topical corticosteroids through the skin can rarely cause adrenal suppression and even Cushing's syndrome (see Section 4.8 'Undesirable effects'and Section 4.9 'Overdose'), depending on the area of the body being treated and the duration of treatment.

Avoid prolonged exposure on the face and keep away from the eyes. Use with caution on broken skin.

On discontinuation of topical corticosteroids a rebound exacerbation of the condition may occur. Prolonged use of compound preparations such as Timodine Cream can increase the likelihood of resistance and of sensitization. Mixing topical preparations on the skin should be avoided where possible; several minutes should elapse between application of different preparations.

Topical corticosteroids are not recommended for acne vulgaris, may worsen secondary infected lesions, and should not be used indiscriminately in pruritis.

Timodine Cream contains butylated hydroxyanisole (E320), cetostearyl alcohol, and sorbic acid which may cause local skin reactions (e.g. contact dermatitis). Butylated hydroxyanisole (E320) may cause irritation to the eyes and mucous membranes. Timodine Cream also contains propyl hydroxybenzoate (E216) and methyl hydroxybenzoate (E218), both of which may cause allergic reactions, which may be delayed. Nystatin can rarely cause contact dermatitis, and allergic reactions can occur after use of benzalkonium chloride.

The elderly

The skin of the elderly is often relatively atrophic so that local and systemic side effects of hydrocortisone are more likely.

Patients with hepatic failure

The reduced metabolism of hydrocortisone in patients with hepatic failure increases the theoretical risk of adrenal suppression.

Paediatric population

Avoid prolonged use in children.

Caution is required in dermatoses of infancy including nappy rash. Care should be taken as the nappy can act as an occlusive dressing and thus allow an increase in absorption of the steroid component of the cream.

In infants, long-term continuous topical steroid therapy should be avoided since this can lead to adrenal suppression even without occlusion. A course of treatment should not normally exceed seven days.

Use of hydrocortisone should be avoided in neonates. Any proposed use of hydrocortisone in neonates should be carefully assessed, as the high body surface area:weight ratio allows a proportionate increase in percutaneous absorption. Consideration should be given to the relative fragility of neonatal skin.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Fertility

No data available

Pregnancy

Topical administration of corticosteroids to pregnant animals can cause abnormalities of foetal development. The relevance of this finding to human beings has not been established. However, topical steroids should not be used extensively in pregnancy, i.e. in large amounts or for prolonged periods.

Lactation

Although poorly absorbed, it is not known whether nystatin enters breast milk. Caution should be exercised when nystatin is prescribed for nursing mothers.

Corticosteroids cross the placenta to varying degrees and may be distributed in small amounts in breast milk. Any topically applied hydrocortisone should be wiped off thoroughly prior to nursing if it is being applied to the breast or nipple area.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Undesirable effects are listed by MedRA System Organ Classes.

Assessment of undesirable effects is based on the following frequency groupings:

Very common:

Common:

Uncommon:

Rare:

Very rare: <1/10,000

Not known: cannot be estimated from the available data

System Organ Class	Frequency	Undesirable Effect
Endocrine disorders	Not known	• adrenal suppression (see Section 4.4 'Special warnings and precautions for use')
Immune system disorders	Not known	• hypersensitivity reactions1
Infections and infestations	Not known	• spread and worsening of untreated infection (see Section 4.4 'Special warnings and precautions for use')
Metabolism and nutrition disorders	Not known	• Cushing's syndrome (see Section 4.4 'Special warnings and precautions for use')
Skin and subcutaneous tissue disorder	Not known	• thinning of the skin2 (see Section 4.4 'Special warnings and precautions for use' and Section 4.9 'Overdose') • irreversible striae atrophicae (see Section 4.9 'Overdose') • telangiectasia (see Section 4.9 'Overdose') • contact dermatitis (see Section 4.4 'Special warnings and precautions for use') • perioral dermatitis • acne or worsening of acne • rosacea • mild depigmentation3 • hypertrichosis • contact sensitisation • purpura • loss of skin collagen and subcutaneous atrophy

1. if signs of hypersensitivity appear, application should stop immediately

2. thinning of the skin may be restored over a period after stopping treatment but the original structure may never return

3. mild depigmentation may be reversible

Exacerbation of symptoms may occur.

4.9 Overdose

Prolonged administration of hydrocortisone, especially to sensitive areas, such as the face and flexures, may result in irreversible adverse effects such as epidermal thinning, telangiectasia and striae. Chronic administration of hydrocortisone may lead to systemic absorption and thereby suppression of the pituitary-adrenal axis. High doses of corticosteroids can cause Cushing's syndrome.

It is possible that nausea and vomiting or diarrhoea may occur after ingestion of this product. Treat symptomatically. A small glass of milk or water may be helpful.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antifungals for topical use

ATC code: D01A

Nystatin

Nystatin is a polyene antifungal antibiotic that interferes with the permeability of the cell membrane of sensitive fungi by binding to sterols, chiefly ergosterol. Nystatin is used for the prophylaxis and treatment of candidiasis of the skin and mucous membranes. It is both fungistatic and fungicidal against a wide range of yeasts and yeast-like fungi.

Dimeticone 350

Dimeticones and other silicones are water-repellent and have a low surface tension. They are used in topical barrier preparations for protecting the skin against water-soluble irritants.

Hydrocortisone

Hydrocortisone is a mild, but effective anti-inflammatory agent.

Benzalkonium chloride solution

Benzalkonium chloride is a quaternary ammonium antiseptic with a broad spectrum of antibacterial activity.

5.2 Pharmacokinetic Properties

Nystatin

Nystatin is poorly absorbed.

Dimeticone 350

Dimeticone is a silicone polymer that is not absorbed.

Hydrocortisone

Hydrocortisone is absorbed through the skin, metabolised in the liver, kidneys and most other body tissues. It is metabolised to hydrogenated and degraded forms such as tetrahydrocortisone and tetrahydrocortisol, which are excreted in the urine mainly conjugated as glucuronides, together with a small proportion of unchanged hydrocortisone (<1%).

Hydrocortisone is extensively bound to plasma proteins, >90%, and has a small volume of distribution, 0.31.kg^-1.

It has a short biological half-life of about 100 minutes and elimination is rapid, with about 90% of the absorbed dose excreted within 24 hours.

Absorption through the skin is greatest where the skin is thin or raw, and from intertriginous areas; it is increased by occlusion.

Benzalkonium chloride solution

Quaternary ammonium salts, such as benzalkonium chloride, are poorly absorbed through the skin.

5.3 Preclinical Safety Data

No preclinical findings of relevance to the prescriber have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Dibutyl phthalate

Glyceryl monostearate SE

Purified water

Stearic acid

Sodium metabisulphite

Cellulose nitrate

Cetostearyl alcohol

Butylated hydroxyanisole compound (containing butylated hydroxyanisole (E320), propyl gallate and citric acid)

Methyl hydroxybenzoate (E218)

Propyl hydroxybenzoate (E216)

Sorbic acid

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store below 15˚C.

6.5 Nature And Contents Of Container

Collapsible aluminium tubes with diaphragm and an internal lacquer coating of araldite resin.

Pack sizes: 5.5 g, 7.5 g and 30 g.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Timodine Cream may cause yellow staining on terry cotton nappies. This will disappear after soaking in bleach or nappy solution followed by rinsing and normal washing.

ADMINISTRATIVE DATA

7. Marketing Authorisation Holder

Alliance Pharmaceuticals Ltd.,

Avonbridge House,

Bath Road,

Chippenham,

Wiltshire,

SN15 2BB

8. Marketing Authorisation Number(S)

PL 16853/0103

9. Date Of First Authorisation/Renewal Of The Authorisation

16^th February 2010

10. Date Of Revision Of The Text

1st September 2011

pseudoephedrine and triprolidine

Generic Name: pseudoephedrine and triprolidine (try PROE li deen and soo doe e FED rin)

Brand names: A-Phedrin, Allerfrim, Allerphed, Altafed, Aphedrid, Aprodine, Biofed-PE, Genac, Histafed, Pediatex TD, Tripohist D, Vi-Sudo, Zymine-D, ...show all 40 brand names.Actifed, Allercon, Triafed, Triposed, Triofed, Actedril, Atridine, Atrofed, Atrogen, Hista-Tabs, LA Nasal Decongestant, Ridifed, Tri-Sudo, Triphed, Triptifed, Actagen, Allerfrin, Triacin, Ritifed, Actacin, Triacting, Trisofed, Pseudocot-T, Sudafed Sinus Nighttime, Zymine DXR, Hist-PSE, Trip-PSE

What is pseudoephedrine and triprolidine?

Triprolidine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Pseudoephedrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of pseudoephedrine and triprolidine is used to treat sneezing, cough, runny or stuffy nose, itchy or watery eyes, hives, skin rash, itching, and other symptoms of allergies and the common cold.

Pseudoephedrine and triprolidine may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about pseudoephedrine and triprolidine?

Do not give this medication to a child younger than 2 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not use any other over-the-counter cold, allergy, or sleep medication without first asking your doctor or pharmacist. If you take certain products together you may accidentally take too much of a certain drug. Read the label of any other medicine you are using to see if it contains an antihistamine or decongestant. Do not use a cough or cold medicine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take cough or cold medicine before the MAO inhibitor has cleared from your body. Pseudoephedrine and triprolidine can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol. It can increase some of the side effects of this medication.

What should I discuss with my healthcare provider before taking pseudoephedrine and triprolidine?

Do not use a cough or cold medicine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take cough or cold medicine before the MAO inhibitor has cleared from your body.

Ask a doctor or pharmacist if it is safe for you to take pseudoephedrine and triprolidine if you have:

• kidney disease;


• 
  

  diabetes;

  
  


• 
  

  glaucoma;

  
  


• 
  

  heart disease or high blood pressure;

  
  


• 
  

  diabetes;

  
  


• 
  

  a thyroid disorder;

  
  


• 
  

  an enlarged prostate; or

  
  


• 
  

  problems with urination.

  
  

This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Pseudoephedrine and triprolidine can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Artificially-sweetened liquid forms of cold medicine may contain phenylalanine. This would be important to know if you have phenylketonuria (PKU). Check the ingredients and warnings on the medication label if you are concerned about phenylalanine.

How should I take pseudoephedrine and triprolidine?

Use this medication exactly as directed on the label, or as it has been prescribed by your doctor. Do not use the medication in larger amounts, or use it for longer than recommended. Cold medicine is usually taken only for a short time until your symptoms clear up.

Do not give this medication to a child younger than 2 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Take this medicine with a full glass of water. Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking or opening the pill would cause too much of the drug to be released at one time.

Measure the liquid form of this medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache, cough, or skin rash.

If you need to have any type of surgery, tell the surgeon ahead of time if you have taken a cold medicine within the past few days.

This medication can cause you to have unusual results with allergy skin tests. Tell any doctor who treats you that you are taking an antihistamine.

Store the medication at room temperature away from moisture and heat.

See also: Pseudoephedrine and triprolidine dosage (in more detail)

What happens if I miss a dose?

Since cold or allergy medicine is usually taken only as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

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

Overdose symptoms may include feeling restless or nervous, nausea, vomiting, stomach pain, dizziness, drowsiness, dry mouth, warmth or tingly feeling, or seizure (convulsions).

What should I avoid while taking pseudoephedrine and triprolidine?

This medication can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol. It can increase some of the side effects of this medication.

Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

Do not use any other over-the-counter cold, allergy, or sleep medication without first asking your doctor or pharmacist. If you take certain products together you may accidentally take too much of a certain drug. Read the label of any other medicine you are using to see if it contains an antihistamine or decongestant.

Pseudoephedrine and triprolidine side effects

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

• 
  

  fast, pounding, or uneven heartbeat;

  
  


• 
  

  confusion, hallucinations, unusual thoughts or behavior;

  
  


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  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


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  increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure);

  
  


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  confusion, hallucinations, unusual thoughts or behavior;

  
  


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  easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms; or

  
  


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  urinating less than usual or not at all.

  
  

Less serious side effects may include:

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  blurred vision;

  
  


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  dry mouth;

  
  


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  nausea, stomach pain, constipation;

  
  


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  mild loss of appetite, stomach upset;

  
  


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  warmth, tingling, or redness under your skin;

  
  


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  sleep problems (insomnia);

  
  


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  restless or excitability (especially in children);

  
  


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  skin rash or itching;

  
  


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  dizziness, drowsiness;

  
  


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  problems with memory or concentration; or

  
  


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  ringing in your ears.

  
  

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

Pseudoephedrine and triprolidine Dosing Information

Usual Adult Dose for Allergic Rhinitis:

Tablets:
Pseudoephedrine-triprolidine 60 mg-2.5 mg
1 tablet orally every 4-6 hours; do not exceed 4 doses in 24 hours.

Syrup:
Pseudoephedrine-triprolidine 30 mg-1.25 mg/mL oral liquid
10 mL orally every 4-6 hours; do not exceed 4 doses in 24 hours.

Liquid:
Pseudoephedrine-triprolidine 10 mg-0.938 mg/mL oral liquid:
2.67 mL orally every 6 hours. Do not take more than 4 doses in 24 hours.
Pseudoephedrine-triprolidine 45 mg-2.5 mg/5 mL oral liquid:
5 to 10 mL orally every 4 to 6 hours. (maximum pseudoephedrine: 240 mg/24 hours).

Usual Adult Dose for Cold Symptoms:

Tablets:
Pseudoephedrine-triprolidine 60 mg-2.5 mg
1 tablet orally every 4-6 hours; do not exceed 4 doses in 24 hours.

Syrup:
Pseudoephedrine-triprolidine 30 mg-1.25 mg/mL oral liquid
10 mL orally every 4-6 hours; do not exceed 4 doses in 24 hours.

Liquid:
Pseudoephedrine-triprolidine 10 mg-0.938 mg/mL oral liquid:
2.67 mL orally every 6 hours. Do not take more than 4 doses in 24 hours.
Pseudoephedrine-triprolidine 45 mg-2.5 mg/5 mL oral liquid:
5 to 10 mL orally every 4 to 6 hours. (maximum pseudoephedrine: 240 mg/24 hours).

Usual Pediatric Dose for Allergic Rhinitis:

Tablets:
Pseudoephedrine-triprolidine 60 mg - 2.5 mg.
6 years to 12 years: 1/2 tablet orally every 4-6 hours; do not exceed 4 doses in 24 hours.
13 years or older: 1 tablet orally every 4-6 hours; do not exceed 4 doses in 24 hours.

Syrup:
Pseudoephedrine-triprolidine 30 mg - 1.25 mg.
6 years to 12 years: 5 mL orally every 4-6 hours; do not exceed 4 doses in 24 hours.
13 years or older: 10 mL orally every 4-6 hours; do not exceed 4 doses in 24 hours.

Liquid:
Pseudoephedrine-triprolidine 10 mg-0.938 mg/mL oral liquid:
6 years to 11 years: 1.33 mL orally every 6 hours. Do not take more than 4 doses in 24 hours.
12 years or older: 2.67 mL orally every 6 hours. Do not take more than 4 doses in 24 hours.
Pseudoephedrine-triprolidine 45 mg-2.5 mg/5 mL oral liquid:
6 years to 11 years: 2.5 to 5 mL orally every 4 to 6 hours. (maximum pseudoephedrine: 120 mg/24 hours).
12 years or older: 5 to 10 mL orally every 4 to 6 hours. (maximum pseudoephedrine: 240 mg/24 hours).

Usual Pediatric Dose for Cold Symptoms:

Tablets:
Pseudoephedrine-triprolidine 60 mg - 2.5 mg.
6 years to 12 years: 1/2 tablet orally every 4-6 hours; do not exceed 4 doses in 24 hours.
13 years or older: 1 tablet orally every 4-6 hours; do not exceed 4 doses in 24 hours.

Syrup:
Pseudoephedrine-triprolidine 30 mg - 1.25 mg.
6 years to 12 years: 5 mL orally every 4-6 hours; do not exceed 4 doses in 24 hours.
13 years or older: 10 mL orally every 4-6 hours; do not exceed 4 doses in 24 hours.

Liquid:
Pseudoephedrine-triprolidine 10 mg-0.938 mg/mL oral liquid:
6 years to 11 years: 1.33 mL orally every 6 hours. Do not take more than 4 doses in 24 hours.
12 years or older: 2.67 mL orally every 6 hours. Do not take more than 4 doses in 24 hours.
Pseudoephedrine-triprolidine 45 mg-2.5 mg/5 mL oral liquid:
6 years to 11 years: 2.5 to 5 mL orally every 4 to 6 hours. (maximum pseudoephedrine: 120 mg/24 hours).
12 years or older: 5 to 10 mL orally every 4 to 6 hours. (maximum pseudoephedrine: 240 mg/24 hours).

What other drugs will affect pseudoephedrine and triprolidine?

Tell your doctor if you regularly use other medicines that make you sleepy (such as narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by pseudoephedrine and triprolidine.

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

• 
  

  medicines to treat high blood pressure;

  
  


• 
  

  a diuretic (water pill);

  
  


• 
  

  medication to treat irritable bowel syndrome;

  
  


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  bladder or urinary medications such as oxybutynin (Ditropan, Oxytrol) or tolterodine (Detrol);

  
  


• 
  

  aspirin or salicylates (such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others);

  
  


• 
  

  a beta-blocker such as atenolol (Tenormin, Tenoretic), carvedilol (Coreg), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), and others; or

  
  


• 
  

  antidepressants such as amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others.

  
  

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

More pseudoephedrine and triprolidine resources

• Pseudoephedrine and triprolidine Side Effects (in more detail)
• Pseudoephedrine and triprolidine Dosage
• Pseudoephedrine and triprolidine Use in Pregnancy & Breastfeeding
• Drug Images
• Pseudoephedrine and triprolidine Drug Interactions
• Pseudoephedrine and triprolidine Support Group
• 8 Reviews for Pseudoephedrine and triprolidine - Add your own review/rating

Compare pseudoephedrine and triprolidine with other medications

• Cold Symptoms
• Hay Fever

Where can I get more information?

• Your pharmacist can provide more information about pseudoephedrine and triprolidine.

See also: pseudoephedrine and triprolidine side effects (in more detail)

Minoxidil

Pronunciation: mi-NOX-i-dil
Generic Name: Minoxidil
Brand Name: Generic only. No brands available.

Minoxidil may cause serious heart problems, including worsening of chest pain. Minoxidil is usually given with beta-blockers to prevent certain heart side effects and with diuretics to prevent serious fluid build-up. If you have severe, uncontrolled high blood pressure or if you take guanethidine, you should only begin taking Minoxidil under direct medical supervision (eg, in a hospital). You will be monitored to prevent side effects, which may occur if your blood pressure lowers too much or too quickly.

Minoxidil is used for:

Lowering high blood pressure in patients who do not respond to other therapy.

Minoxidil is a vasodilator. It reduces blood pressure by relaxing and dilating (widening) blood vessels. Blood flows more freely and at a lower pressure through dilated blood vessels.

Do NOT use Minoxidil if:

• you are allergic to any ingredient in Minoxidil


• you have a tumor of the adrenal gland (pheochromocytoma)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Minoxidil:

Some medical conditions may interact with Minoxidil. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have blood flow problems, congestive heart failure or other heart problems, or have had a heart attack


• if you have kidney problems or are on dialysis

Some MEDICINES MAY INTERACT with Minoxidil. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Guanethidine because lightheadedness, especially upon standing, may occur

This may not be a complete list of all interactions that may occur. Ask your health care provider if Minoxidil may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Minoxidil:

Use Minoxidil as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Minoxidil. Talk to your pharmacist if you have questions about this information.


• Take Minoxidil by mouth with or without food.


• If you miss a dose of Minoxidil, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Minoxidil.

Important safety information:

• Minoxidil may cause dizziness, lightheadedness, or changes in vision. These effects may be worse if you take it with alcohol or certain medicines. Use Minoxidil with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Minoxidil may cause dizziness, lightheadedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects.


• Patients who take medicine for high blood pressure often feel tired or run down for a few weeks after starting treatment. Be sure to take your medicine even if you may not feel "normal." Tell your doctor if you develop any new symptoms.


• Weigh yourself daily while you are taking Minoxidil. Check with your doctor if you quickly gain 5 pounds or more or if there is swelling or puffiness of the face, hands, ankles or stomach.


• Lab tests, including electrolyte counts, may be performed while you use Minoxidil. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Minoxidil while you are pregnant. Minoxidil is found in breast milk. Do not breast-feed while taking Minoxidil.

Possible side effects of Minoxidil:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Changes in body hair; excessive hair growth; mild weight gain; nausea; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); changes in hearing or vision; difficulty breathing; excessive, sudden weight gain; fainting; lightheadedness; increased chest, arm, or shoulder pain; increased heart rate; pounding heartbeat; swelling.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include fainting; fast pulse; lightheadedness.

Proper storage of Minoxidil:

Store Minoxidil between 68 and 77 degrees F (20 and 25 degrees C). Store in a tightly closed container. Store away from heat, moisture, and light. Keep Minoxidil out of the reach of children and away from pets.

General information:

• If you have any questions about Minoxidil, please talk with your doctor, pharmacist, or other health care provider.


• Minoxidil is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Minoxidil. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Minoxidil resources

• Minoxidil Dosage
• Minoxidil Use in Pregnancy & Breastfeeding
• Drug Images
• Minoxidil Drug Interactions
• Minoxidil Support Group
• 0 Reviews for Minoxidil - Add your own review/rating

• Minoxidil Prescribing Information (FDA)


• Minoxidil Monograph (AHFS DI)


• Minoxidil Professional Patient Advice (Wolters Kluwer)


• minoxidil Concise Consumer Information (Cerner Multum)


• minoxidil Advanced Consumer (Micromedex) - Includes Dosage Information


• Loniten Prescribing Information (FDA)

Compare Minoxidil with other medications

• High Blood Pressure

Stavudine Capsules

FULL PRESCRIBING INFORMATION

WARNING: LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS; PANCREATITIS

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Warnings and Precautions (5.1)].

Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression [see Warnings and Precautions (5.4)].

Indications and Usage for Stavudine Capsules

Stavudine Capsules, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14)].

Stavudine Capsules Dosage and Administration

The interval between doses of Stavudine Capsules should be 12 hours. Stavudine Capsules may be taken with or without food.

Recommended Adult Dosage

The recommended adult dosage is based on body weight as follows:

• For patients weighing less than 60 kg: 30 mg every 12 hours.


• For patients weighing at least 60 kg: 40 mg every 12 hours.

Recommended Pediatric Dosage

• For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours.


• For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours.


• For pediatric patients weighing at least 30 kg: use the recommended adult dosage.

Dosage Adjustment

Renal Impairment

Adult Patients

Stavudine Capsules may be administered to adult patients with impaired renal function with an adjustment in dosage as shown in Table 1.

Table 1: Recommended Dosage Adjustment for Adult Patients with Renal Impairment

* Administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis days.
Creatinine Clearance (mL/min)	Recommended Stavudine Dose by Patient Weight
	at least 60 kg	less than 60 kg
greater than 50	40 mg every 12 hours	30 mg every 12 hours
26 to 50	20 mg every 12 hours	15 mg every 12 hours
10 to 25	20 mg every 24 hours	15 mg every 24 hours
Hemodialysis	20 mg every 24 hours*	15 mg every 24 hours*

 

Pediatric Patients

Since urinary excretion is also a major route of elimination of stavudine in pediatric patients, the clearance of stavudine may be altered in children with renal impairment. There are insufficient data to recommend a specific dose adjustment of Stavudine Capsules in this patient population.

Dosage Forms and Strengths

• The 15 mg capsules have a hard-shell gelatin capsule with an off-white opaque cap and a pink opaque body filled with a white to off-white powder. The capsule is axially printed with M 154 in black ink on both the cap and body.


• The 20 mg capsules have a hard-shell gelatin capsule with a pink opaque cap and a pink opaque body filled with a white to off-white powder. The capsule is axially printed with M 155 in black ink on both the cap and body.


• The 30 mg capsules have a hard-shell gelatin capsule with an off-white opaque cap and a light orange opaque body filled with a white to off-white powder. The capsule is axially printed with M 137 in black ink on both the cap and body.


• The 40 mg capsules have a hard-shell gelatin capsule with a light orange opaque cap and a light orange opaque body filled with a white to off-white powder. The capsule is axially printed with M 138 in black ink on both the cap and body.

Contraindications

Stavudine Capsules are contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.

Warnings and Precautions

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Although relative rates of lactic acidosis have not been assessed in prospective well controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing stavudine. Female gender, obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Use in Specific Populations (8.1)].

Particular caution should be exercised when administering stavudine to any patient with known risk factors for liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain and unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms, including motor weakness [see Warnings and Precautions (5.3)] might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome.

Treatment with stavudine should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Permanent discontinuation of stavudine should be considered for patients with confirmed lactic acidosis.

Hepatic Toxicity

The safety and efficacy of stavudine have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Hepatotoxicity and hepatic failure resulting in death were reported during post-marketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine and stavudine. This combination should be avoided [see Adverse Reactions (6)].

Use with Interferon and Ribavirin-based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as stavudine. Although no evidence of a pharmacokinetic or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was seen when ribavirin was coadministered with stavudine in HIV-1/HCV co-infected patients [see Drug Interactions (7)],  hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon and ribavirin. Patients receiving interferon with or without ribavirin and stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of stavudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh > 6) (see the full prescribing information for interferon and ribavirin).

Neurologic Symptoms

Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). If motor weakness develops, stavudine should be discontinued. Symptoms may continue or worsen following discontinuation of therapy.

Peripheral sensory neuropathy, manifested by numbness, tingling or pain in the hands or feet, has been reported in patients receiving stavudine therapy. Peripheral neuropathy, which can be severe, is dose related and occurs more frequently in patients with advanced HIV-1 disease, a history of peripheral neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine [see Adverse Reactions (6)].

Patients should be monitored for the development of peripheral neuropathy. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. If peripheral neuropathy develops permanent discontinuation of stavudine should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy.

Pancreatitis

Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. The combination of stavudine and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring; avoid use in combination with didanosine.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.

In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving stavudine should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using stavudine including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including stavudine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning and Warnings and Precautions (5.1)]


• hepatic toxicity [see Warnings and Precautions (5.2)]


• neurologic symptoms and motor weakness [see Warnings and Precautions (5.3)]


• pancreatitis [see Boxed Warning and Warnings and Precautions (5.4)]


• lipoatrophy/lipodystrophy [see Warnings and Precautions (5.5)]

When stavudine is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when stavudine is used alone.

Clinical Trial Experience in Adults

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Selected adverse reactions that occurred in adult patients receiving stavudine in a controlled monotherapy study (Study AI455-019) are provided in Table 2.

Table 2: Selected Adverse Reactions in Study AI455-019* (Monotherapy)

* The incidences reported included all severity grades and all reactions regardless of causality. † Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks
Adverse Reaction	Percent (%)
	Stavudine† (40 mg twice daily) (n = 412)	Zidovudine (200 mg 3 times daily) (n = 402)
Headache	54	49
Diarrhea	50	44
Peripheral Neurologic      Symptoms/Neuropathy	52	39
Rash	40	35
Nausea and Vomiting	39	44

Pancreatitis was observed in three of the 412 adult patients who received stavudine in study AI455-019.

Selected adverse reactions that occurred in antiretroviral-naive adult patients receiving stavudine from two controlled combination studies are provided in Table 3.

Table 3: Selected Adverse Reactions* in START 1 and START 2† Studies (Combination Therapy)

* The incidences reported included all severity grades and all reactions regardless of causality. † START 2 compared two triple-combination regimens in 205 treatment-naive patients. Patients received either stavudine (40 mg twice daily) plus didanosine plus indinavir or zidovudine plus lamivudine plus indinavir. ‡ Duration of stavudine therapy = 48 weeks
Adverse Reaction	Percent (%)
	START 1		START 2†
	Stavudine + Lamivudine + Indinavir (n = 100‡)	Zidovudine + Lamivudine + Indinavir (n = 102)	Stavudine + Didanosine + Indinavir (n = 102‡)	Zidovudine + Lamivudine + Indinavir (n = 103)
Nausea	43	63	53	67
Diarrhea	34	16	45	39
Headache	25	26	46	37
Rash	18	13	30	18
Vomiting	18	33	30	35
Peripheral Neurologic      Symptoms/Neuropathy	8	7	21	10

Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 4.

Table 4: Selected Laboratory Abnormalities in Study AI455-019*†

ULN = upper limit of normal
* Data presented for patients for whom laboratory evaluations were performed. † Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks
Parameter	Percent (%)
	Stavudine (40 mg twice daily) (n = 412)	Zidovudine (200 mg 3 times daily) (n = 402)
AST (SGOT) (> 5 x ULN)	11	10
ALT (SGPT) (> 5 x ULN)	13	11
Amylase (≥ 1.4 x ULN)	14	13

Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6.

Table 5: Selected Laboratory Abnormalities in START 1 and START 2 Studies (Grades 3 to 4)

ULN = upper limit of normal.
Parameter	Percent (%)
	START 1		START 2
	Stavudine + Lamivudine + Indinavir (n = 100)	Zidovudine + Lamivudine + Indinavir (n = 102)	Stavudine + Didanosine + Indinavir (n = 102)	Zidovudine + Lamivudine + Indinavir (n = 103)
Bilirubin (> 2.6 x ULN)	7	6	16	8
AST (SGOT) (> 5 x ULN)	5	2	7	7
ALT (SGPT) (> 5 x ULN)	6	2	8	5
GGT (> 5 x ULN)	2	2	5	2
Lipase (> 2 x ULN)	6	3	5	5
Amylase (> 2 x ULN)	4	< 1	8	2

 

Table 6: Selected Laboratory Abnormalities in START 1 and START 2 Studies (All Grades)

Parameter	Percent (%)
	START 1		START 2
	Stavudine + Lamivudine + Indinavir (n = 100)	Zidovudine + Lamivudine + Indinavir (n = 102)	Stavudine + Didanosine + Indinavir (n = 102)	Zidovudine + Lamivudine + Indinavir (n = 103)
Total Bilirubin	65	60	68	55
AST (SGOT)	42	20	53	20
ALT (SGPT)	40	20	50	18
GGT	15	8	28	12
Lipase	27	12	26	19
Amylase	21	19	31	17

 

Clinical Trial Experience in Pediatric Patients

Adverse reactions and serious laboratory abnormalities reported in pediatric patients from birth through adolescence during clinical trials were similar in type and frequency to those seen in adult patients [see Use in Specific Populations (8.4)].

Post-marketing Experience

The following adverse reactions have been identified during post-marketing use of stavudine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to stavudine, or a combination of these factors.

Body as a Whole: abdominal pain, allergic reaction, chills/fever and redistribution/accumulation of body fat [see Warnings and Precautions (5.5)].

Digestive Disorders: anorexia.

Exocrine Gland Disorders: pancreatitis, including fatal cases [see Warnings and Precautions (5.4)].

Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia and macrocytosis.

Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.1)], hepatitis and liver failure.

Metabolic Disorders: lipoatrophy, lipodystrophy [see Warnings and Precautions (5.5)], diabetes mellitus and hyperglycemia.

Musculoskeletal: myalgia.

Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis) [see Warnings and Precautions (5.1, 5.3)].

Use with Didanosine- and Hydroxyurea-based Regimens

When stavudine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when stavudine is used alone. Thus, patients treated with stavudine in combination with didanosine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see Warnings and Precautions (5)]. The combination of stavudine and hydroxyurea, with or without didanosine, should be avoided.

Drug Interactions

Stavudine is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.

Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with stavudine should be avoided.

Doxorubicin: In vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin. The clinical significance of this interaction is unknown; therefore, concomitant use of stavudine with doxorubicin should be undertaken with caution.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine and zidovudine. The clinical significance of the interaction with stavudine is unknown; therefore, concomitant use of stavudine with ribavirin should be undertaken with caution. No pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10) or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.2)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects

Pregnancy Category C

Reproduction studies have been performed in rats and rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence of teratogenicity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure, while no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. An increase in early rat neonatal mortality (birth to 4 days of age) occurred at 399 times the human exposure, while survival of neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. Animal reproduction studies are not always predictive of human response.

There are no adequate and well controlled studies of stavudine in pregnant women. Stavudine should be used during pregnancy only if the potential benefit justifies the potential risk.

Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues [see Boxed Warning and Warnings and Precautions (5.1)].The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to stavudine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that stavudine is excreted in milk. Although it is not known whether stavudine is excreted in human milk, there exists the potential for adverse effects from stavudine in nursing infants. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving stavudine.

Pediatric Use

Use of stavudine in pediatric patients from birth through adolescence is supported by evidence from adequate and well controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients [see Dosage and Administration (2.2) and Adverse Reactions (6.2)].

Adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of stavudine in adults. These studies include ACTG 240, where 105 pediatric patients ages 3 months to 6 years received stavudine 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received stavudine 2 mg/kg/day either alone or in combination with didanosine from birth through 6 weeks of age; and a clinical trial where 8 newborns received stavudine 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age.

Stavudine pharmacokinetics have been evaluated in 25 HIV-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after IV or oral administration of single doses and twice-daily regimens and in 30 HIV-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens [see Clinical Pharmacology (12.3, Table 9)].

Geriatric Use

Clinical studies of stavudine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of stavudine cannot be ruled out.

In a monotherapy Expanded Access Program for patients with advanced HIV-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy.

Stavudine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3)].

Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Overdosage

Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 mL/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied.

Stavudine Capsules Description

Stavudine (d4T) is a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus type 1 (HIV-1). The chemical name for stavudine is 2',3'-didehydro-3'-deoxythymidine. Stavudine has the following structural formula:

Stavudine, USP is a white to off-white crystalline solid with the molecular formula C10H12N2O4 and a molecular weight of 224.21. The solubility of stavudine at 23°C is approximately 83 mg/mL in water and 30 mg/mL in propylene glycol. The n-octanol/water partition coefficient of stavudine at 23°C is 0.144.

Stavudine Capsules, USP are supplied for oral administration in strengths of 15 mg, 20 mg, 30 mg or 40 mg of stavudine, USP. Each capsule also contains inactive ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The empty hard shell gelatin capsules contain gelatin and titanium dioxide. In addition, the 15 mg empty capsules contain D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6; the 20 mg empty capsules contain D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40; the 30 mg empty capsules contain D&C Red No. 28, D&C Yellow No. 10, FD&C Red No. 40, FD&C Yellow No. 6; and the 40 mg empty capsules contain D&C Red No. 28, D&C Yellow No. 10, FD&C Yellow No. 6.

The imprinting ink contains black iron oxide, potassium hydroxide, propylene glycol and shellac.

Stavudine Capsules - Clinical Pharmacology

Mechanism of Action

Stavudine is an antiviral drug [see Clinical Pharmacology (12.4)].

Pharmacokinetics

The pharmacokinetics of stavudine have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). Peak plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of stavudine with repeated administration every 6, 8, or 12 hours.

Absorption

Following oral administration, stavudine is rapidly absorbed, with peak plasma concentrations occurring within one hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution. Steady-state pharmacokinetic parameters of stavudine in HIV-1-infected adults are shown in Table 7.

Table 7: Steady-State Pharmacokinetic Parameters of Stavudine in HIV-1-Infected

AUC0-24 = Area under the curve over 24 hours Cmax = Maximum plasma concentration Cmin = Trough or minimum plasma concentration
Parameter	Stavudine 40 mg BID Mean ± SD (n = 8)
AUC0-24 (ng•h/mL)  Cmax (ng/mL) Cmin (ng/mL)	2568 ± 454 536 ± 146 8 ± 9

 

Distribution

Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 mcg/mL. Stavudine distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 8.

Metabolism

Metabolism plays a limited role in the clearance of stavudine. Unchanged stavudine was the major drug-related component circulating in plasma after an 80 mg dose of 14C-stavudine, while metabolites constituted minor components of the circulating radioactivity. Minor metabolites include oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine.

Elimination

Following an 80 mg dose of 14C-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and feces, respectively. Radioactivity due to parent drug in urine and feces was 73.7% and 62%, respectively. The mean terminal elimination half-life is approximately 2.3 hours following single oral doses. Mean renal clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of the apparent oral clearance.

In HIV-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 8). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.