Regaine for Women Regular Strength

1. Name Of The Medicinal Product

Regaine for Women Regular Strength

2. Qualitative And Quantitative Composition

Minoxidil 20 mg/ml (2% w/v).

Contains propylene glycol.

For full list of excipients see section 6.1.

3. Pharmaceutical Form

Cutaneous Solution (to be applied to the scalp).

4. Clinical Particulars

4.1 Therapeutic Indications

Regaine for Women Regular Strength is indicated for the treatment of alopecia androgenetica in women aged between 18 and 65.

Onset and degree of hair regrowth may be variable among users. Although trends in the data suggest that those users who are younger, whose hair has been thinning for a shorter period of time or who have a smaller area of thinning on the vertex are more likely to respond to Regaine for Women Regular Strength, individual responses cannot be predicted.

4.2 Posology And Method Of Administration

Women aged 18-65:

Hair and scalp should be thoroughly dry prior to topical application of Regaine for Women Regular Strength. A dose of 1 ml Regaine for Women Regular Strength cutaneous solution should be applied to the total affected areas of the scalp twice daily. The total dosage should not exceed 2 ml. If fingertips are used to facilitate drug application, hands should be washed afterwards.

It may take twice daily applications for four months or more before evidence of hair growth can be expected.

If hair re-growth occurs, twice daily applications of Regaine for Women Regular Strength are necessary for continued hair growth. Anecdotal reports indicate that re-grown hair may disappear three to four months after stopping Regaine for Women Regular Strength application and the balding process will continue.

Users should discontinue treatment if there is no improvement after one year.

The method of application varies according to the disposable applicator used:

Pump spray applicator: this is useful for large areas. Aim the pump at the centre of the bald area, press once and spread with fingertips over the entire bald area. Repeat for a total of 6 times to apply a dose of 1 ml. Avoid breathing spray mist.

Extended spray-tip applicator: this is useful for small areas, or under hair. The pump spray applicator must be in place in order to use this additional applicator. Use in the same way as the pump spray.

Rub-on applicator: squeeze the upright bottle once to fill the 1 ml chamber to the black line. Invert bottle, dab on scalp, and spread Regaine for Women Regular Strength over the entire bald area until chamber is empty.

Children and the Elderly

Not recommended. The safety and effectiveness of Regaine for Women Regular Strength in users aged under 18 or over 65 has not been established.

4.3 Contraindications

Regaine for Women Regular Strength is contra-indicated:

− in users with a history of sensitivity to minoxidil, ethanol, or propylene glycol

− in users with treated or untreated hypertension

− in users with any scalp abnormality (including psoriasis and sunburn)

− in users with a shaved scalp

− if occlusive dressings or other topical medical preparations are being used.

4.4 Special Warnings And Precautions For Use

Before using Regaine for Women Regular Strength, the user should determine that the scalp is normal and healthy.

Minoxidil is only indicated for the treatment of alopecia androgenetica and should not be used in other types of hair loss for example when there is no family history of hair loss, hair loss is sudden and/or patchy, hair loss is due to childbirth or the reason for hair loss is unknown.

The patient should stop using Regaine for Women Regular Strength and see a doctor if hypotension is detected or if the patient is experiencing chest pain, rapid heart beat, faintness or dizziness, sudden unexplained weight gain, swollen hands or feet or persistent redness.

Patients with known cardiovascular disease or cardiac arrhythmia should contact a physician before using Regaine for Women Regular Strength.

Regaine for Women Regular Strength is for external use only. Do not apply to areas of the body other than the scalp.

Hands should be washed thoroughly after applying the solution. Inhalation of the spray mist should be avoided.

Regaine for Women Regular Strength contains ethanol (alcohol), which will cause burning and irritation of the eye. In the event of accidental contact with sensitive surfaces (eye, abraded skin and mucous membranes) the area should be bathed with large amounts of cool tap water.

Regaine for Women Regular Strength contains propylene glycol, which may cause skin irritation.

Some patients have experienced changes in hair colour and/or texture with use of Regaine for Women Regular Strength.

Patients should be advised to consult their doctor or pharmacist if they are concerned at any time during treatment with Regaine for Women Regular Strength.

Some consumers reported increased hair shedding upon initiation of therapy with Regaine for Women Regular Strength. This is most likely due to minoxidil's action of shifting hairs from the resting telogen phase to the growing anagen phase (old hairs fall out as new hairs grow in their place). This temporary increase in hair shedding generally occurs two to six weeks after beginning treatment and subsides within a couple of weeks. If shedding persists (>2 weeks), users should stop using Regaine for Women Regular Strength and consult their doctor.

Users should be aware that, whilst extensive use of Regaine for Women Regular Strength has not revealed evidence that sufficient minoxidil is absorbed to have systemic effects, greater absorption because of misuse, individual variability, unusual sensitivity or decreased integrity of the epidermal barrier caused by inflammation or disease processes in the skin (e.g. excoriations of the scalp, or scalp psoriasis) could lead, at least theoretically, to systemic effects.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Topical drugs, such as corticosteroids, tretinoin, dithranol or petrolatum, which alter the stratum corneum barrier, could result in increased absorption of minoxidil if applied concurrently. Although it has not been demonstrated clinically, there exists the theoretical possibility of absorbed minoxidil potentiating orthostatic hypotension caused by peripheral vasodilators.

4.6 Pregnancy And Lactation

There are no adequate and well controlled studies in pregnant women.

Animal studies have shown a risk to the foetus at exposure levels that are very high compared to those intended for human exposure (see section 5.3). The potential risk in humans is unknown.

Systemically absorbed minoxidil is secreted in human milk.

Regaine for Women Regular Strength should not be used during pregnancy or lactation.

4.7 Effects On Ability To Drive And Use Machines

Based on the pharmacodynamic and overall safety profile of minoxidil, it is not expected that Regaine for Women Regular Strength would interfere with the ability to drive or operate machinery.

4.8 Undesirable Effects

In placebo controlled trials, the overall frequency of adverse events in females in all body system categories was approximately five times that of males.

Several thousand patients have used topical minoxidil in clinical trials where a comparison with an inactive solution was made. Dermatological reactions (e.g. irritation, itching) occurred in patients using both solutions. This has been explained by the presence of propylene glycol in both the active and inactive solution.

Data from 7 placebo controlled trials are available with a population of 1,197 males and females treated with topical minoxidil solution (2% and 5% combined) where adverse events were assessed. Additionally, adverse events reported in post-marketing are included.

The frequency of adverse reactions to topical minoxidil solution is defined using the following convention:

Very common (

Body system	Incidence	Reported adverse event
Nervous system disorders	Common	Headache
Vascular disorders	Uncommon:	Hypotension
Respiratory, thoracic and mediastinal disorders	Uncommon:	Dyspnoea
Skin and subcutaneous tissue disorders	Common:	Hypertrichosis (unwanted non-scalp hair including facial hair growth in women), pruritus (including rash pruritic and application site, generalized and eye pruritus
Uncommon:	Temporary hair loss (see section 4.4), changes in hair texture and hair colour, skin exfoliation (including application site, exfoliative rash and dermatitis exfoliative), rash (including application site, pustular, papular, generalized vestibular and macular rash), acne (acne form rash), dermatitis (including contact, application site, allergic, atopic and seborrhoeic dermatitis) and dry skin (including application site dryness)
General disorders and administration site conditions	Uncommon:	Oedema peripheral, Application site irritation (including skin irritation), application site erythema (including erythema and rash erythematous)

Users should stop using Regaine for Women Regular Strength if they experience chest-pain, tachycardia, faintness, dizziness, sudden unexplained weight gain, swollen hands or feet or persistent redness or irritation of the scalp.

4.9 Overdose

Increased systemic absorption of minoxidil may potentially occur if higher-than-recommended doses of Regaine for Women Regular Strength are applied to larger surface areas of the body or areas other than the scalp.

Because of the concentration of minoxidil in Regaine for Women Regular Strength, accidental ingestion has the potential of producing systemic effects related to the pharmacological action of the drug (5 ml of Regaine for Women Regular Strength contains 100 mg minoxidil; the maximum recommended adult dose for oral minoxidil administration in the treatment of hypertension). Signs and symptoms of minoxidil overdosage would primarily be cardiovascular effects associated with sodium and water retention, tachycardia and hypotension.

Treatment

Treatment of minoxidil overdosage should be symptomatic and supportive.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other dermatologicals, ATC code: D11AX

Individual responses to Regaine for Women Regular Strength are variable and unpredictable.

The effect of Regaine for Women Regular Strength has been assessed in phase III clinical trials in women conducted over a 48 week treatment period.

In these studies Regaine for Women Regular Strength was compared to the product vehicle without the minoxidil active ingredient. The primary efficacy criterion was non-vellus hair count in a 1.0 cm² reference area of affected scalp. The mean changes observed in this parameter in these studies were significantly in favour of Regaine and were as follows:

Mean change in non-vellus hair count in reference 1 cm2 area of scalp compared with baseline
	Regaine for Women Regular Strength (minoxidil 2%)	Vehicle	Pairwise comparison
Baseline	150.4	138.4
	Mean change from baseline	Mean change from baseline
16 weeks	+35.9	+20.0	2>vehicle
32 weeks	+26.7	+15.2	2>vehicle
48 weeks	+20.7	+9.4	2>vehicle

Using non-vellus hair count as an efficacy criteria, Regaine for Women Regular Strength has also been shown to stabilise hair loss (defined as re-growth or no loss) in 88% of patients compared with 69% of patients who received vehicle in one trial following 48 weeks treatment and in 87% of patients compared with 73% of patients who received vehicle in a further trial following 32 weeks treatment.

Female patients' own evaluations in clinical studies have shown that hair growth was reported by approximately 60% of females after 8 months of Regaine for Women Regular Strength usage.

Patient evaluation of visible hair growth
	% of Females reporting re-growth after 8 months Regaine for Women Regular Strength usage	% of Females reporting re-growth after 4 months Product vehicle usage
Minimal re-growth	30-40	29-33
Moderate to dense re-growth	20-25	7-12
Total	55-59	40-41

In addition, Regaine for Women Regular Strength has been shown to stabilise hair loss (shown as re-growth or no loss) in 4 out of 5 females as calculated from two clinical studies that showed stabilisation with 88 and 87% respectively while corresponding figures for vehicle were 69 and 74%.

The mechanism by which minoxidil stimulates hair growth is not fully understood, but minoxidil can reverse the hair loss process of androgenetic alopecia by the following means:

- increase the diameter of the hair shaft

- stimulate anagen growth

- prolong the anagen phase

- stimulate anagen recovery from the telogen phase

As a peripheral vasodilator minoxidil enhances microcirculation to hair follicles. The Vascular Endothelial Growth Factor (VEGF) is stimulated by minoxidil and VEGF is presumably responsible for the increased capillary fenestration, indicative of a high metabolic activity, observed during the anagen phase.

5.2 Pharmacokinetic Properties

The failure to detect evidence of systemic effects during treatment with Regaine solution reflects the poor absorption of topically applied minoxidil from normal intact skin. Systemic absorption of minoxidil from topically applied solution ranges between 1% and 2% of the total applied dose.

In a study in males, the minoxidil serum concentration time curve (AUC) for the 2% solution averaged 7.54 ng·h/ml compared to a mean AUC of 35.1 ng·h/ml for the 2.5 mg oral formulation. The mean peak plasma concentration (C_max) for the topical solution was 1.25 ng/ml, compared to 18.5 ng/ml following the 2.5 mg oral dose.

There is some evidence from in vitro studies that minoxidil reversibly binds to human plasma proteins. However, since only 1 – 2% of topically applied minoxidil is absorbed, the extent of plasma protein binding occurring in vivo after topical application would be clinically insignificant. The volume of distribution of minoxidil after intravenous administration has been estimated at 70 litres.

Approximately 60% minoxidil absorbed after topical application is metabolised to minoxidil glucuronide, primarily in the liver. Minoxidil and its metabolites are excreted almost entirely in the urine, with a very minor degree of elimination via the faeces. Following cessation of dosing, approximately 95% of topically applied minoxidil will be eliminated within four days.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Cardiac effects of minoxidil in dogs are species-specific in terms of the low doses that cause profound haemodynamic effects and associated changes in the heart. Available data indicate that similar cardiac effects do not occur in humans treated topically or orally with minoxidil.

Mutagenicity

Minoxidil showed no evidence of mutagenic/genotoxic potential in a number of in vitro and in vivo assays.

Teratogenicity

Animal reproduction toxicity studies in rats and rabbits have shown signs of maternal toxicity and a risk to the foetus at exposure levels that are very high compared to those intended for human exposure (from 19 to 570-fold human exposure). A low, albeit remote, risk of foetal harm is possible in humans.

Fertility

Preclinical fertility studies in rats have shown minoxidil doses equal to or greater than 3 mg/kg/day (at least 21-fold human exposure) when administered orally and greater than 9 mg/kg/day (at least 64-fold human exposure) when administered subcutaneously were associated with reduced conception and implantation rates as well as a reduction in the number of live pups.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene glycol

Ethanol

Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

48 months

6.4 Special Precautions For Storage

Regaine for Women Regular Strength is flammable. Do not store above 25°C.

6.5 Nature And Contents Of Container

HDPE bottle with spray-pump/dabbing applicator containing 60 ml of solution.

Pack size: 1 x 60 ml.

6.6 Special Precautions For Disposal And Other Handling

The solution is flammable. Do not use while smoking, or near any naked flame or strong heat source. Avoid exposure of the container and contents to naked flames during use, storage and disposal. Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0149

9. Date Of First Authorisation/Renewal Of The Authorisation

7^th March 2005/27 Feb 2009

10. Date Of Revision Of The Text

6 October 2010

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levothyroxine

lee-voe-thye-ROX-een

Oral route(Tablet)

Thyroid hormones, including levothyroxine, should not be used either alone or with other therapeutic agents for the treatment of obesity or weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects .

Commonly used brand name(s)

In the U.S.

• Levothroid


• Levoxyl


• Synthroid


• Tirosint


• Unithroid

Available Dosage Forms:

• Tablet


• Capsule, Liquid Filled

Therapeutic Class: Thyroid Supplement

Uses For levothyroxine

Levothyroxine is used to treat hypothyroidism, a condition where the thyroid gland does not produce enough thyroid hormone. Levothyroxine is also used to help decrease the size of enlarged thyroid glands (also called a goiter) and to treat thyroid cancer.

levothyroxine is available only with your doctor's prescription.

Importance of Diet

Certain foods may affect how levothyroxine works in the body. Dose adjustments may be needed if you or your child routinely consume any of the following:

• Cotton seed meal.


• Dietary fiber.


• Soybean flour (infant formula).


• Walnuts.

Before Using levothyroxine

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 levothyroxine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to levothyroxine 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 performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of levothyroxine in children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of levothyroxine in the elderly. However, elderly patients are more likely to have age-related heart problems, which may require caution and an adjustment in the dose for patients receiving levothyroxine.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	A	Adequate studies in pregnant women have not shown an increased risk of fetal abnormalities.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during 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 levothyroxine, 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 levothyroxine 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.

• Acenocoumarol


• Aluminum Carbonate, Basic


• Aluminum Hydroxide


• Aluminum Phosphate


• Anisindione


• Calcium Acetate


• Calcium Carbonate


• Calcium Citrate


• Cholestyramine


• Chromium


• Colesevelam


• Conjugated Estrogens


• Dicumarol


• Dihydroxyaluminum Aminoacetate


• Dihydroxyaluminum Sodium Carbonate


• Eltrombopag


• Esterified Estrogens


• Estradiol


• Estriol


• Estrone


• Estropipate


• Imatinib


• Iron


• Kelp


• Lanthanum Carbonate


• Lopinavir


• Magaldrate


• Magnesium Carbonate


• Magnesium Hydroxide


• Magnesium Oxide


• Magnesium Trisilicate


• Phenindione


• Phenprocoumon


• Phenytoin


• Rifampin


• Rifapentine


• Ritonavir


• Sevelamer


• Simvastatin


• Sodium Polystyrene Sulfonate


• Soybean


• Warfarin

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using levothyroxine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use levothyroxine, or give you special instructions about the use of food, alcohol, or tobacco.

• Enteral Nutrition

Other Medical Problems

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

• Abnormal heart rhythms (arrhythmias), history of or


• Angina, history of or


• Blood vessel disease, history of or


• Heart disease, history of or


• Osteoporosis, history of—Use with caution. May make these conditions worse.

• Adrenal gland insufficiency (underactive adrenal gland), untreated or


• Heart attack, recent or


• Thyrotoxicosis (overactive thyroid), untreated—Should not use in patients with these conditions.

Proper Use of levothyroxine

levothyroxine will need to be taken for the rest of your life or your child's life. Do not stop taking levothyroxine or change your dose without first checking with your doctor. It may take several weeks before you start to notice that your symptoms are better.

It is best to take levothyroxine on an empty stomach. Take it with a full glass of water at least 30 minutes to 1 hour before eating breakfast.

levothyroxine should be taken at least 4 hours before or 4 hours after these medicines: antacids (Maalox®, Mylanta®, or Tums®), calcium supplements, cholestyramine (Prevalite®, Questran®), colestipol (Colestid®), iron supplements, orlistat (Alli®, Xenical®), simethicone (Gas-X®, Mylicon®), and sucralfate (Carafate®).

For infants and children who cannot swallow the tablet form, the tablet can be crushed and mixed with a small amount of water (5 to 10 milliliters [mL] or 1 to 2 teaspoonfuls). You may use a spoon or dropper to give the mixture. Use the mixture right away and do not store it to use later.

Dosing

The dose of levothyroxine 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 levothyroxine. 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 form (tablet):
  
  • For hypothyroidism:
    
    • Older adults—The dose is based on body weight and must be determined by your doctor. The usual dose is less than 1 microgram (mcg) per kilogram (kg) per day.
    
    
    • Adults and teenagers—The dose is based on body weight and must be determined by your doctor. The usual dose is 1.7 micrograms (mcg) per kilogram (kg) per day.
    
    
    • Children older than 12 years of age—The dose is based on body weight and must be determined by your doctor. The usual dose is 2 to 3 mcg per kg per day.
    
    
    • Children 6 to 12 years of age—The dose is based on body weight and must be determined by your doctor. The usual dose is 4 to 5 mcg per kg per day.
    
    
    • Children 1 to 5 years of age—The dose is based on body weight and must be determined by your doctor. The usual dose is 5 to 6 mcg per kg per day.
    
    
    • Children 6 to 12 months of age—The dose is based on body weight and must be determined by your doctor. The usual dose is 6 to 8 mcg per kg per day.
    
    
    • Children 3 to 6 months of age—The dose is based on body weight and must be determined by your doctor. The usual dose is 8 to 10 mcg per kg per day.
    
    
    • Children 0 to 3 months of age—The dose is based on body weight and must be determined by your doctor. The usual dose is 10 to 15 mcg per kg per day.
    
    
  
  

Missed Dose

If you miss a dose of levothyroxine, 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 levothyroxine

It is very important that your doctor check the progress of you or your child at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. Blood and urine tests will be needed to check for unwanted effects.

Levothyroxine should not be used for the treatment of obesity or for the purpose of losing weight. levothyroxine is not effective for weight reduction. If taken in large amounts, levothyroxine may cause serious unwanted effects.

Hypothyroidism can sometimes cause infertility in men and women. Levothyroxine should not be used for the treatment of infertility unless it is caused by hypothyroidism.

For patients with diabetes, it is very important that you keep track of your blood or urine sugar levels as instructed by your doctor. Check with your doctor right away if you notice any changes in your sugar levels.

If you think you have become pregnant while using levothyroxine, tell your doctor right away. You may need a larger dose of levothyroxine while you are pregnant.

Women who use levothyroxine for a long time may have some bone loss, which could lead to osteoporosis. Talk with your doctor if you have questions or concerns about this.

Call your doctor right away if you or your child start to have rapid or irregular heartbeats, chest pain, shortness of breath, leg cramps, headaches, nervousness, irritability, sleeplessness, tremors, a change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, a fever, changes in menstrual periods, hives, or a skin rash. These could be symptoms of too much medicine in your body.

Make sure any doctor or dentist who treats you knows that you or your child are using levothyroxine. You may need to stop using levothyroxine several days before having surgery or medical tests.

A temporary loss of hair may occur during the first few months of levothyroxine therapy. Ask your doctor about this if you have any concerns.

levothyroxine 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:

Less common

• Chest pain or discomfort


• decreased urine output


• difficult or labored breathing


• difficulty with swallowing


• dilated neck veins


• extreme fatigue


• fainting


• fast, slow, irregular, pounding, or racing heartbeat or pulse


• fever


• heat intolerance


• hives or welts


• increased blood pressure


• increased pulse


• irregular breathing


• irritability


• menstrual changes


• nausea


• pain or discomfort in the arms, jaw, back, or neck


• shortness of breath


• skin itching, rash, or redness


• sweating


• swelling of the eyes, face, lips, throat, or tongue


• tightness in the chest


• tremors


• troubled breathing


• wheezing

Rare

• Blurred or double vision


• dizziness


• eye pain


• lack or slowing of normal growth in children


• limp or walk favoring one leg


• pain in the hip or knee


• seizures


• severe headache

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

Symptoms of Overdose

• Change in consciousness


• cold clammy skin


• confusion


• disorientation


• fast or weak pulse


• lightheadedness


• loss of consciousness


• sudden headache


• sudden loss of coordination


• sudden slurring of speech

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:

Less common

• Abdominal cramps


• change in appetite


• crying


• diarrhea


• false or unusual sense of well-being


• fear


• feeling not well or unhappy


• feeling of discomfort


• feeling of warmth


• feeling things are not real


• feelings of suspicion and distrust


• hair loss


• headache


• increased appetite


• mental depression


• muscle weakness


• nervousness


• quick to react or overreact emotionally


• rapidly changing moods


• redness of the face, neck, arms, and occasionally, upper chest


• restlessness


• sleeplessness


• trouble getting pregnant


• trouble sitting still


• trouble sleeping


• unable to sleep


• unusual tiredness or weakness


• vomiting


• weight gain


• weight loss

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: levothyroxine side effects (in more detail)

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Zidovudine

Class: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: 3′-Azido-3′-deoxythymidine
CAS Number: 30516-87-1
Brands: Combivir, Retrovir, Trizivir

Special Alerts:

[Posted 03/01/2011] ISSUE: FDA updated the public about an ongoing safety review of abacavir and a possible increased risk of heart attack. There has been conflicting information on the potential increased risk of heart attack with abacavir (Ziagen) treatment. An increased risk of heart attack (myocardial infarction or MI) has been seen in several observational studies and one randomized controlled trial (RCT) with abacavir. However, an increased risk of heart attack has not been seen in other RCTs and the safety database maintained by the drug manufacturer.

FDA conducted a meta-analysis of 26 randomized clinical trials that evaluated abacavir. This meta-analysis did not show an increased risk of MI associated with the use of abacavir. FDA will continue to communicate any new safety information to the public as it becomes available.

BACKGROUND: Abacavir is an antiviral medication used in combination with other antiretroviral drugs [abacavir and lamivudine (Epzicom); abacavir, lamivudine, and zidovudine (Trizivir)] for the treatment of HIV-1 infection.

RECOMMENDATION: Healthcare professionals should continue to prescribe abacavir according to the professional label. Patients should not stop taking their abacavir without first talking to their healthcare professional. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for zidovudine to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

• 
  

  Hematologic toxicity reported, particularly in patients with advanced disease.^{1 231} (See Hematologic Effects under Cautions.)

  
  


• 
  

  Symptomatic myopathy reported.^{1 231} (See Musculoskeletal Effects under Cautions.)

  
  


• 
  

  Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported rarely in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs) alone or in conjunction with other antiretrovirals.^{1 231} (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  
  


• 
  

  If using Trizivir, consider that abacavir has been associated with serious and sometimes fatal hypersensitivity reactions.¹⁰

  
  

Introduction

Antiretroviral; nucleoside reverse transcriptase inhibitor (NRTI).^{1 4 7 12 16 18 29 39 47 231 260 296}

Uses for Zidovudine

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.^{1 231 279 466}

An alternative (not a preferred) NRTI for use in multiple-drug antiretroviral regimens for initial therapy in adults.²⁷⁹

Fixed-combination preparation containing zidovudine and lamivudine (Combivir) used in conjunction with other antiretrovirals.²⁷¹

Fixed-combination preparation containing zidovudine, abacavir, and lamivudine (Trizivir) used for triple NRTI treatment;¹⁰ can be used alone or in conjunction with other antiretrovirals.¹⁰ If using Trizivir, consider that data are limited regarding use of the fixed combination in patients with higher viral loads (>100,000 copies/mL) at baseline.¹⁰

Because of inferior antiretroviral activity, a triple NRTI regimen of abacavir, lamivudine, and zidovudine is not recommended for initial therapy.²⁷⁹

Prevention of Maternal-fetal Transmission of HIV

Prevention of maternal-fetal transmission of HIV.^{1 231 279 455}

A regimen that includes combination antiretroviral therapy or prophylaxis in the pregnant women, intrapartum therapy, and zidovudine prophylaxis in the newborn is recommended for the prevention of perinatal HIV transmission.⁴⁵⁵ Antiretroviral therapy or antiretroviral prophylaxis for prevention of perinatal HIV transmission during the antepartum period recommended for all pregnant HIV-infected women in the US; zidovudine should be included in the regimen when feasible.⁴⁵⁵ Intrapartum zidovudine in conjunction with other antiretroviral agents is recommended in all pregnant HIV-infected women.⁴⁵⁵ Administration of zidovudine for 6 weeks is recommended for all HIV-exposed infants.⁴⁵⁵

If intrapartum/newborn zidovudine is used for prevention of perinatal HIV transmission in women in labor who received no prior antiretroviral therapy, some clinicians would add single-dose intrapartum/newborn nevirapine (a nevirapine dose given to the mother at onset of labor and a nevirapine dose given to the neonate).⁴⁵⁵

If a single-dose nevirapine regimen in conjunction with intrapartum/newborn zidovudine is used for prevention of perinatal HIV transmission in women in labor who received no prior antiretroviral therapy, some clinicians suggest that consideration be given to adding a zidovudine and lamivudine regimen in the mother to reduce development of nevirapine resistance.⁴⁵⁵

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 risk for transmission of the virus.^{96 97 98 149 194 224 337 338 339 340 341 342 343 344 418 464 465} Used in conjunction with other antiretrovirals.⁴⁶⁴

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.⁵⁰³ Used in conjunction with other antiretrovirals.⁵⁰³

Zidovudine Dosage and Administration

Administration

Administer orally or by intermittent or continuous IV infusion.^{1 231} Should not be administered by rapid or bolus IV injection, IM injection, or sub-Q injection.²³¹

Oral Administration

Administer single-entity preparations (Retrovir) and fixed-combination preparations (Combivir, Trizivir) orally without regard to meals.^{1 10 271}

To reduce risk of esophageal irritation and ulceration, zidovudine capsules should be administered while the patient is in an upright position and with adequate amounts of fluid (e.g., at least 120 mL of water).¹⁸⁴

For children, zidovudine oral solution can be used.¹ Alternatively, children who can reliably swallow an intact tablet or capsule may receive zidovudine tablets or capsules.¹

Because dosage of zidovudine and lamivudine cannot be adjusted individually, the fixed-combination containing zidovudine and lamivudine (Combivir) should not be used in individuals requiring dosage adjustment, including children <12 years of age, patients with impaired renal function (i.e., Cl_cr <50 mL/minute), patients with impaired hepatic function, and patients who experience dose-limiting adverse effects.²⁷¹

Because dosage of the drugs cannot be adjusted individually, the fixed-combination containing abacavir, lamivudine, and zidovudine (Trizivir) should not be used in pediatric patients; adolescents or adults with low body weight (i.e., <40 kg); patients with impaired renal function (i.e., Cl_cr <50 mL/minute); patients with impaired hepatic function; or patients who experience dose-limiting adverse effects.¹⁰

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Oral zidovudine should replace parenteral zidovudine as soon as feasible.²³¹

Dilution

Zidovudine concentrate for IV infusion containing 10 mg/mL must be diluted prior to administration.²³¹ The appropriate dose should be withdrawn from the vial and diluted in 5% dextrose injection to provide a solution containing ≤4 mg/mL.²³¹

Rate of Administration

Intermittent IV infusions should be infused at a constant rate over 60 minutes.²³¹

In neonates, intermittent IV infusions should be infused at a constant rate over 30 minutes.²³¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Used in conjunction with other antiretrovirals for treatment of HIV infection or for postexposure prophylaxis of HIV;^{1 231 271} may be used alone or in conjunction with other antiretrovirals for prevention of maternal-fetal transmission of HIV.^{1 231} The fixed-combination preparation containing zidovudine, abacavir, and lamivudine may be used alone or in conjunction with other antiretrovirals.¹⁰

Dosage of Combivir and Trizivir expressed as number of tablets.^{10 271}

IV dosing regimen of 1 mg/kg every 4 hours is equivalent to an oral regimen of 100 mg every 4 hours.²³¹

Modification of zidovudine dosage is necessary in adults or pediatric patients who develop anemia and/or neutropenia.^{1 91 92 229 231 244 245 451} Substantial anemia (hemoglobin <7.5 g/dL or a reduction >25% from baseline) and/or neutropenia (granulocyte count <750/mm³ or a reduction >50% from baseline) may require dose interruption until evidence of bone marrow recovery occurs.^{1 231} If bone marrow recovery occurs following interruption of therapy, reinitiation of zidovudine therapy may be appropriate.^{1 231} (See Hematologic Effects under Cautions.)

Pediatric Patients

Treatment of HIV Infection

To avoid medication errors, use extra care in calculating the dose, transcribing the medication order, dispensing the prescription, and providing dosing instructions.¹

Oral

Premature neonates: 2 mg/kg every 12 hours; frequency of administration may be increased to every 8 hours at 2 weeks of age in neonates with ≥30 weeks gestation at birth or at 4 weeks of age in those with <30 weeks gestation at birth.^{455 466}

Neonates and infants <6 weeks of age: 2 mg/kg every 6 hours.⁴⁶⁶

Zidovudine Dosage in Pediatric Patients ≥6 Weeks of Age Who Weigh ≥4 kg 1

Body Weight (kg)	Dosage Regimen
4 to <9	12 mg/kg twice daily or 8 mg/kg 3 times daily
9 to <30	9 mg/kg twice daily or 6 mg/kg 3 times daily
≥30	300 mg twice daily or 200 mg 3 times daily

Alternatively, for pediatric patients ≥6 weeks of age, 240 mg/m² twice daily or 160 mg/m² 3 times daily.¹

Combivir: 1 tablet twice daily in adolescents ≥12 years of age.^{271 466}

Trizivir: 1 tablet twice daily in adolescents weighing ≥40 kg.^{10 466}

IV

Premature neonates: 1.5 mg/kg every 12 hours; the frequency of administration may be increased to every 8 hours at 2 weeks of age in neonates with ≥30 weeks gestation at birth or at 4 weeks of age in those with <30 weeks gestation at birth.^{455 466}

Neonates and infants <6 weeks of age: 1.5 mg/kg every 6 hours.⁴⁶⁶

Infants and children 6 weeks to 12 years of age: 120 mg/m² by intermittent IV infusion every 6 hours; alternatively, 20 mg/m² per hour by continuous IV infusion.⁴⁶⁶

Prevention of Maternal-fetal Transmission of HIV

Postexposure Prophylaxis

Oral

Premature neonates: Initiate therapy with 2 mg/kg every 12 hours; frequency of administration may be increased to every 8 hours at 2 weeks of age in neonates with >30 to <35 weeks gestation at birth or at 4 weeks of age in those with <30 weeks gestation at birth.^{455 466} Zidovudine is continued through 6 weeks of age.⁴⁵⁵

Neonates ≥35 weeks at gestation: 2 mg/kg every 6 hours starting within 6–12 hours after birth and continued through 6 weeks of age.^{1 231 455 458}

Used in conjunction with intrapartum zidovudine in the mother.⁴⁶⁶

IV

Premature neonates: Initiate therapy with 1.5 mg/kg every 12 hours; frequency of administration may be increased to every 8 hours at 2 weeks of age in neonates with ≥30 to <35 weeks gestation at birth or at 4 weeks of age in those with <30 weeks gestation at birth.^{455 466} Zidovudine is continued through 6 weeks of age.⁴⁵⁵

Neonates ≥35 weeks at gestation: 1.5 mg/kg every 6 hours starting within 6–12 hours after birth.^{1 231 455} Zidovudine is continued through 6 weeks of age.⁴⁵⁵

Used in conjunction with intrapartum zidovudine in the mother.⁴⁶⁶

Adults

Treatment of HIV Infection

Oral

600 mg daily in divided doses.^{1 3 279 466 483 484 485 486 487 488 489 490 497} Usually given in a dosage of 200 mg 3 times daily or 300 mg twice daily.^{3 279 466}

Combivir: 1 tablet twice daily.^{271 279}

Trizivir: 1 tablet twice daily.^{10 279} Patient should weigh ≥40 kg.¹⁰

IV

1 mg/kg 5 to 6 times daily (5 to 6 mg/kg daily).²³¹ Higher dosage may be associated with greater improvement of neurologic symptoms in patients with preexisting neurologic disease.²³¹

Prevention of Maternal-fetal Transmission of HIV

Oral

IV

At start of labor, 2 mg/kg over 1 hour followed by 1 mg/kg per hour given by continuous IV infusion until the umbilical cord is clamped.^{1 231 455}

Used in conjunction with a 6-week zidovudine regimen in the neonate.^{466 455}

Postexposure Prophylaxis of HIV†

Occupational Exposure†

Oral

200 mg 3 times daily or 300 mg twice daily.⁴⁶⁴

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.^{464 467 470}

Nonoccupational Exposure†

Oral

200 mg 3 times daily or 300 mg twice daily.⁵⁰³

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.⁵⁰³

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Oral

Children 6 weeks to 12 years of age: Maximum 200 mg every 8 hours.¹

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Insufficient clinical experience to recommend dosage adjustment for patients with mild to moderate hepatic impairment or liver cirrhosis; a reduction in dosage may be necessary in these patients and frequent monitoring for hematologic toxicities advised.^{1 231}

Renal Impairment

Treatment of HIV Infection

Oral

100 mg every 6 to 8 hours for patients with end-stage renal disease maintained on hemodialysis or peritoneal dialysis.¹

IV

1 mg/kg every 6 to 8 hours for patients with end-stage renal disease maintained on hemodialysis or peritoneal dialysis.²³¹

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.^{1 231}

Cautions for Zidovudine

Contraindications

• 
  

  History of clinically important hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to zidovudine or any ingredient in the formulation.^{1 231}

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Hematologic Effects

Use with caution in patients who have compromised bone marrow function (i.e., hemoglobin concentration <9.5 g/dL or granulocyte count <1000/mm³).^{1 231}

Anemia and/or neutropenia reported; these events are especially important in patients with advanced symptomatic HIV disease.^{1 2 3 4 29 30 33 38 62 64 65 82 106 107 134 139 231 260 332} Pancytopenia reported; pancytopenia usually reversible following discontinuation of zidovudine.^{1 231}

Blood cell counts and indices of anemia (e.g., hemoglobin, mean corpuscular volume) should be determined prior to and monitored during zidovudine therapy.^{1 50 64 181 231 332} Patients with advanced HIV disease or low baseline blood cell counts and indices of anemia should be monitored frequently^{1 231} (at least every 2 weeks);^{181 231} periodic monitoring^{1 231} (once monthly for the first 3 months and then, if stable, once every 3 months) recommended for patients with asymptomatic or early symptomatic HIV infection.¹⁸¹

If anemia and/or neutropenia occurs, interruption of zidovudine therapy and/or dosage adjustment may be necessary.^{1 231} In patients who develop substantial anemia, interruption of zidovudine therapy does not necessarily eliminate the need for transfusions.^{1 231}

Musculoskeletal Effects

Myopathy and myositis with pathologic changes, similar to that produced by HIV disease, associated with long-term use of zidovudine.^{1 231}

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving zidovudine.^{1 271} Reported most frequently in women; obesity and long-term NRTI therapy also may be risk factors.^{1 271} Has been reported in patients with no known risk factors.^{1 271}

Use with caution in patients with known risk factors for liver disease.^{1 271}

Interrupt therapy if there are clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).^{1 271}

General Precautions

Do not use multiple zidovudine-containing preparations concomitantly.^{1 271}

Incidence of adverse effects increases with disease progression; monitor patients carefully, especially as disease progression occurs.^{1 231}

Use of Fixed Combinations

When used in fixed combination with lamivudine (Combivir), consider the cautions, precautions, and contraindications associated with lamivudine.²⁷¹

When used in fixed combination with abacavir and lamivudine (Trizivir), consider the cautions, precautions, and contraindications associated with the concomitant agents.¹⁰

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.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]); this may necessitate further evaluation and treatment.¹

Specific Populations

Pregnancy

Category C.^{1 231} Antiretroviral Pregnancy Registry at 800-258-4263.^{1 231}

The preferred NRTI for use in antiretroviral regimens in pregnant women based on efficacy studies and extensive experience.²⁷⁹ Pregnancy registry data indicate no increased risk for congenital abnormalities among infants born to women who receive zidovudine during pregnancy compared with general population.^{453 455}

Lactation

Distributed into human milk.^{1 231}

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

Pediatric Use

Studied in neonates perinatally exposed to HIV and in HIV-infected pediatric patients >3 months of age.^{1 231}

The major adverse effects reported in children are similar to those reported in adults^{1 91 92 114 163 244 245} and include bone marrow toxicity resulting in anemia and/or neutropenia.^{1 91 92 114 155 231 244 245}

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.^{1 231} No substantial differences in response relative to younger adults identified.^{1 231}

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.^{1 231}

Hepatic Impairment

Possibility of increased risk of hematologic toxicity in patients with severe hepatic impairment.^{1 231}

Use with caution in patients with known risk factors for liver disease.^{1 231}

Renal Impairment

Dosage adjustment recommended in patients with severe renal impairment (Cl_cr <15 mL/minute).^{1 231} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Adults: Headache, malaise, anorexia, nausea, vomiting.^{1 231}

Children: Fever, cough, GI disorders.¹

Interactions for Zidovudine

Specific Drugs

Drug	Interaction	Comments
Abacavir	Pharmacokinetic interactions unlikely161 In vitro evidence of synergistic antiretroviral effects161
Acetaminophen	Pharmacokinetic interactions unlikely156
Acyclovir	Increased toxicity reported;15 has been used concomitantly without increased toxicity61 181
Antifungals, azoles (fluconazole)	Increased zidovudine AUC with fluconazole1 231 457	Routine dosage adjustment not needed;1 231 monitor for zidovudine-associated adverse effects457 Consider reduction in zidovudine dosage if patient experiences severe anemia or other severe events1 231
Antimycobacterials, rifamycins (rifabutin, rifampin)	Pharmacokinetic interactions unlikely with rifabutin409 Decreased zidovudine AUC with rifampin1 150 231
Atazanavir	No change in zidovudine AUC, but possible decreased zidovudine concentrations279 In vitro evidence of additive antiretroviral effects507	Clinical importance unknown279
Atovaquone	Increased zidovudine AUC; no change in pharmacokinetics of atovaquone1 231 242 Possible increased hematologic toxicity242	Routine dosage adjustments not needed1 231
Cidofovir	No pharmacokinetic interaction with cidofovir; cidofovir must be given concomitantly with probenecid and probenecid can reduce zidovudine clearance243	Temporarily discontinue zidovudine or reduce zidovudine dosage by 50% on days that cidofovir and probenecid are given243
Co-trimoxazole	Pharmacokinetic interactions unlikely333
Cytotoxic/Myelosuppressive agents	Increased risk of hematologic toxicity1 29 176 231 332	Use with caution29 176 332
Darunavir	Ritonavir-boosted darunavir: Pharmacokinetic interaction unlikely510
Delavirdine	Pharmacokinetic interactions unlikely284 In vitro evidence of additive or synergistic antiretroviral effects1 175 284 391 406
Didanosine	Pharmacokinetic interactions unlikely279 422 In vitro evidence of synergistic antiretroviral effects281
Doxorubicin	In vitro evidence of antagonism1 227 231	Concomitant use should be avoided1 231
Efavirenz	Pharmacokinetic interactions unlikely175 In vitro evidence of synergistic antiretroviral effects1 175 284 391 406	Dosage adjustment not needed175
Emtricitabine	In vitro evidence of additive or synergistic antiretroviral effectsb
Fosamprenavir	Studies using amprenavir indicate possible increased amprenavir AUC;d possible increased zidovudine plasma concentrations and AUCd In vitro evidence of synergistic antiretroviral effectsd
Ganciclovir	No clinically important pharmacokinetic interactions279 Increased risk of hematologic toxicity196 197 201 213 278 279	Concomitant use not recommended196 197 201 213 278
Indinavir	In vitro evidence of additive or synergistic antiretroviral effects166 215 480 481 482
Interferon (interferon alfa, peginterferon alfa)	Possible increased risk of potentially fatal hepatic decompensation in patients coinfected with hepatitis C virus (HCV) and HIV who are receiving interferon alfa, ribavirin, and antiretroviral agents1 f Increased risk of hematologic toxicity (e.g., neutropenia, thrombocytopenia) and hepatic toxicity in patients receiving interferon alfa or peginterferon alfa, ribavirin, and zidovudine1 231 395 399 f In vitro evidence of synergistic antiretroviral effects34 57 351 395 396 397 398 399	Monitor for adverse effects1 231 395 399 f If zidovudine used in patients receiving interferon alfa or peginterferon alfa (with or without ribavirin), closely monitor for toxicities, especially hepatic decompensation; consider discontinuing zidovudine as appropriate; if worsening toxicities (e.g., hepatic decompensation Child-Pugh >6) are observed, consider discontinuing or reducing dosage of interferon or peginterferon alfa and/or ribavirin1 f
Lamivudine	Pharmacokinetic interactions unlikely1 231 In vitro evidence of synergistic antiretroviral effects347
Lopinavir	Possible decreased zidovudine concentrations508	Clinical importance unknown508
Megestrol acetate	Slight decrease in zidovudine AUC102	Not considered clinically important102
Methadone	Increased zidovudine AUC; no change in pharmacokinetics of methadone1 231 279 350	Routine dosage adjustment not needed; monitor for zidovudine toxicity1 231 279
Nelfinavir	Decreased zidovudine peak plasma concentrations and AUC; no effect on nelfinavir pharmacokinetics1 215 231 In vitro evidence of additive or synergistic antiretroviral effects166 215 480 481 482	Routine dosage adjustment not needed1 215 231
Nevirapine	Decreased plasma zidovudine concentrations391 In vitro evidence of synergistic antiretroviral effects1 175 284 391 406
Oxazepam	Pharmacokinetic interactions unlikely353
Phenytoin	Pharmacokinetic interactions; alteration in pharmacokinetics of both drugs reported1 231	Use with caution; monitor closely1 231
Probenecid	Increased zidovudine peak plasma concentrations and AUC1 231	Routine dosage adjustment not needed1 231
Ribavirin	Ribavirin can reduce phosphorylation of zidovudine;37 60 279 no evidence of pharmacokinetic or pharmacodynamic interaction in patients coinfected with HCV and HIV1 Possible increased risk of potentially fatal hepatic decompensation in patients coinfected with HCV and HIV who are receiving interferon alfa or peginterferon alfa, ribavirin, and antiretroviral agents1 f	Concomitant use should be avoided if possible or closely monitor virologic response and hematologic toxicities 279 If zidovudine used in patients receiving interferon alfa or peginterferon alfa (with or without ribavirin), closely monitor for toxicities, especially hepatic decompensation; consider discontinuing zidovudine as appropriate; if worsening toxicities (e.g., hepatic decompensation Child-Pugh >6) are observed, consider discontinuing or reducing dosage of interferon and/or ribavirin1 f
Ritonavir	Decreased zidovudine peak plasma concentrations and AUC; no effect on ritonavir pharmacokinetics1 231 481 In vitro evidence of additive or synergistic antiretroviral effects166 215 480 481 482	Routine dosage adjustment not needed1 231
Saquinavir	In vitro evidence of additive or synergistic antiretroviral effects166 215 480 481 482
Stavudine	In vitro evidence of antagonism1 165 231	Concomitant use not recommended1 231 279
Tipranavir	Ritonavir-boosted tipranavir: Decreased zidovudine AUC279 e In vitro evidence of additive antiretroviral effectse	Clinical importance unknowne Appropriate dosages for concomitant use with ritonavir-boosted tipranavir not established279 e
Valproic acid	Increased zidovudine AUC1 231	Routine dosage adjustment not needed; monitor for zidovudine toxicity1 231 279 Consider reduction in zidovudine dosage if patient experiences severe anemia or other severe events1 231

Zidovudine Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration; peak plasma concentrations achieved within 0.5–1.5 hours.^{1 2 4 110 111 115 116 117 119} Bioavailability is 64%.¹

Commercially available tablets, capsules, and oral solution are bioequivalent.¹

Food

Extent of absorption (AUC) not affected by food.¹

Special Populations

Zidovudine AUC increased in patients with renal impairment.^{1 177 231}

Zidovudine pharmacokinetics in pediatric patients >3 months of age similar to that in adults; bioavailability is 61% in infants 14 days to 3 months of age and 65% in pediatric patients 3 months to 12 years of age.¹ Bioavailability is greater in neonates ≤14 days of age and is reported to be 89%.¹

Pharmacokinetics of zidovudine in pregnant women are similar to those reported in nonpregnant adults.^{1 231}

Distribution

Extent

Widely distributed.^{1 32 231}

Distributed into CSF; ^{1 32 67 114 148 177 231} the ratio of CSF/plasma concentrations reported in adults or children with HIV infection is 0.15–2.1.^{1 32 67 114 115 148 177 231}

Distributed into semen.^{110 145 159 160}