Tiaprizal may be available in the countries listed below.
Tiapride hydrochloride (a derivative of Tiapride) is reported as an ingredient of Tiaprizal in the following countries:
International Drug Name Search
Epaq may be available in the countries listed below.
Metronidazole is reported as an ingredient of Epaq in the following countries:
Salbutamol sulfate (a derivative of Salbutamol) is reported as an ingredient of Epaq in the following countries:
International Drug Name Search
Treating inflammation and itching due to certain skin conditions.
Diflorasone Diacetate Cream is a topical corticosteroid. It works by reducing skin inflammation (redness, swelling, itching, and irritation).
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Diflorasone Diacetate Cream. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Diflorasone Diacetate Cream. Because little, if any, of Diflorasone Diacetate Cream is absorbed into the blood, the risk of it interacting with another medicine is low.
This may not be a complete list of all interactions that may occur. Ask your health care provider if Diflorasone Diacetate Cream 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.
Use Diflorasone Diacetate Cream as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Diflorasone Diacetate Cream.
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:
Dryness; itching.
Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); acne-like rash; burning, cracking, irritation, itching, or peeling not present before you began using Diflorasone Diacetate Cream; excessive hair growth; inflamed hair follicles; inflammation around the mouth; muscle weakness; thinning, softening, or discoloration of the skin; unusual weight gain, especially in the face.
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.
See also: Diflorasone Diacetate side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Store Diflorasone Diacetate Cream at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Keep Diflorasone Diacetate Cream out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Diflorasone Diacetate Cream. 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.
Class: 5-alpha-Reductase Inhibitors
VA Class: HS900
Chemical Name: 5α,17β)-N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide
Molecular Formula: C27H30F6N2O2
CAS Number: 164656-23-9
Brands: Avodart
Special Alerts:
[Posted 06/09/2011] ISSUE: FDA notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).
BACKGROUND: The new safety information is based on FDA’s review of two large, randomized controlled trials––the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. Finasteride (Proscar), dutasteride (Avodart), and dutasteride in combination with tamsulosin (marketed combination product as Jalyn) are approved to improve symptoms of an enlarged prostate gland (benign prostatic hyperplasia or BPH). Proscar and Avodart are also approved to reduce the risk of urinary retention or surgery related to an enlarged prostate. Finasteride (Propecia) is approved to treat male pattern hair loss.
RECOMMENDATION: Prior to initiating therapy with 5-ARIs, perform appropriate evaluation to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH). See Drug Safety Communication for a Data Summary and additional information. For more information visit the FDA website at: and .
Selective inhibitor of steroid 5α-reductase isoenzymes, which are necessary for conversion of testosterone to 5α-dihydrotestosterone (DHT).1 4 9
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 symptomatic BPH1 to improve symptoms and reduce the risk of acute urinary retention and the need for surgery.1 3 Ineffective in patients who do not have evidence of prostatic enlargement.11
Although drug therapy usually is not as effective as surgical therapy, it may provide adequate symptomatic relief with fewer and less serious adverse effects compared with surgery.11
Steroid 5α-reductase inhibitors may be a useful alternative to surgery in patients with obstructive manifestations who are unwilling to undergo surgical correction of BPH;8 may aid those who may be at increased risk from, but not necessarily candidates for, prostate surgery.4 8 10 Also may be considered in patients who have symptomatic prostatic enlargement but whose symptoms are not bothersome (i.e., do not interfere with activities of daily living) in order to prevent progression of the disease.11
May consider combined therapy with an α1-adrenergic blocker and 5α-reductase inhibitor for men with bothersome moderate to severe BPH and demonstrable prostatic enlargement.11 Has been more effective than therapy with either drug alone in preventing long-term BPH symptom progression.11 Men at risk for BPH progression are most likely to benefit from combination therapy.11
Administer orally without regard to meals.1
The capsules should be swallowed whole.1
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.
Initially and for maintenance therapy, 0.5 mg once daily.1
While early symptomatic improvement (e.g., within 3 months) may occur, ≥6 months of therapy may be necessary to determine clinical benefit.2 Generally, therapy is continued for life.9
No specific dosage recommendations for hepatic impairment.1 (See Hepatic Impairment under Cautions.)
Dosage adjustment not required.1
Dosage adjustment not required.1
Known or suspected pregnancy.1 (See Fetal/Neonatal Morbidity and also Pregnancy under Cautions.)
Use in women or children.1
Known hypersensitivity to dutasteride, other 5α-reductase inhibitors, or any ingredient in the formulation.1
May cause fetal harm; teratogenicity demonstrated in animals.1 Animal studies indicate adverse effects on embryofetal development of male fetuses exposed to the drug during pregnancy (e.g., abnormalities of the external genitalia, decreased prostatic and seminal vesicular weights, distended preputial glands, nipple development).1
Because of the potential for absorption through the skin and the subsequent potential risk to a male fetus, pregnant women or women who may become pregnant should not handle the capsules.1 2
If contact is made with leaking capsules, wash the affected area immediately with soap and water.1 2
To prevent potential fetal exposure, men receiving the drug should not donate blood during dutasteride therapy and for at least 6 months following discontinuance of the drug.1
Seminal drug concentrations not sufficient to warrant the use of condoms to prevent exposure to dutasteride.10
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.
Evaluate candidates for dutasteride therapy for other urologic conditions that might mimic BPH, such as infection,4 prostate 1 4 or bladder cancer,4 stricture disease,4 uncontrolled diabetes mellitus,4 neurogenic bladder,4 or CHF.4 7
Perform digital rectal examinations, as well as other screening tests for prostate cancer, before initiating therapy and periodically thereafter.1 7 8
Monitor patients with a large residual urinary volume and/or severely diminished urinary flow carefully for obstructive uropathy.4 7 Such patients may not be candidates for dutasteride therapy,1 and may require surgery.4 7
Decreases PSA concentrations; may interfere with interpretation of serum PSA determinations.1 (See Specific Drugs and Laboratory Tests under Interactions.)
Category X.1 (See Fetal/Neonatal Morbidity and also Contraindications under Cautions.)
Not known whether dutasteride is distributed into milk, but use of the drug is contraindicated in women.1 10
Safety and efficacy not established, but the drug is not indicated for use in children.1
No substantial differences in safety and efficacy relative to younger men.1
Not studied in patients with hepatic impairment.1 Increased exposure to the drug is probable.1 Use with caution.1
Impotence, decreased libido, ejaculation disorder, gynecomastia (breast tenderness, enlargement).1
Metabolized by CYP isoenzymes 3A4 and 3A5 to active metabolites; not metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.1
Potential pharmacokinetic interaction with inhibitors of CYP3A4 (decreased clearance and increased serum concentrations of dutasteride).1
Drug or Test | Interaction | Comments |
|---|---|---|
Amlodipine | Pharmacokinetic interaction unlikely1 | |
Cholestyramine | Pharmacokinetic or pharmacodynamic interaction unlikely1 | |
Cimetidine | Decreased clearance and increased serum concentrations of dutasteride1 | Use concomitantly with care |
Ciprofloxacin | Decreased clearance and increased serum concentrations of dutasteride1 | Use concomitantly with care1 |
Digoxin | Pharmacokinetic or pharmacodynamic interaction unlikely1 | |
Diltiazem | Decreased clearance and increased serum concentrations of dutasteride1 | Not considered clinically important1 |
Ketoconazole | Decreased clearance and increased serum concentrations of dutasteride1 | Use concomitantly with care1 |
Ritonavir | Decreased clearance and increased serum concentrations of dutasteride1 | |
Tamsulosin | Pharmacokinetic or pharmacodynamic interaction unlikely1 | |
Terazosin | Pharmacokinetic or pharmacodynamic interaction unlikely1 | |
Test for PSA | 50% decrease in serum PSA concentration after ≥6 months of treatment1 3 6 9 10 No substantial change in ratio of free to total PSA (percentage of free PSA)1 | Establish a new baseline PSA 3–6 months after initiation of treatment1 For clinical interpretation of isolated PSA values in men receiving dutasteride for ≥6 months, double the reported value for PSA for comparison with normal values in men not receiving the drug1 3 No adjustment of reported value of ratio appears to be necessary1 |
Troleandomycin | Decreased clearance and increased serum concentrations of dutasteride1 | |
Verapamil | Decreased clearance and increased serum concentrations of dutasteride1 | Not considered clinically important1 |
Warfarin | Pharmacokinetic or pharmacodynamic interaction unlikely1 |
Absolute bioavailability is approximately 60%.1
Reduces serum and prostatic 5α-dihydroxytestosterone (DHT) concentrations maximally within 1–2 weeks of initiation of therapy.1
Serum drug concentrations are detectable for up to 4–6 months following discontinuance of therapy.1
Decreases peak serum concentrations.1 Not considered clinically important.1
Widely distributed; volume of distribution is 300–500 L.1
Distributes into semen.1
Highly bound to albumin (99%) and α-1 acid glycoprotein (96.6%).1
Metabolized by CYP3A4 and CYP3A5 to active metabolites.1
Excreted in the feces (45%) and urine (<1%) mainly as metabolites; approximately 55% remained unaccounted.1
Terminal half-life is approximately 5 weeks at steady state.1
In patients with hepatic impairment, pharmacokinetics not studied.1 Metabolized extensively in the liver, and increased exposure to the drug is probable in hepatic impairment.1
In adolescents (<18 years of age), pharmacokinetics not studied.1
In patients with renal impairment, pharmacokinetics not studied; however, <0.1% of a dose is excreted in urine in healthy individuals.1
In women, pharmacokinetics not studied; use contraindicated.1
Effects of race on pharmacokinetics not studied.1
25°C (may be exposed to 15–30°C).1
Competitive inhibitor of both the type 1 and type 2 isoenzymes of steroid 5α-reductase.1 9 These enzymes convert testosterone to DHT.1 9
Reduces serum and prostatic DHT concentrations substantially.1 DHT appears to be the principal androgen responsible for initial development and subsequent enlargement of the prostate gland.1 9
Increases serum testosterone (generally remaining within the normal range) and prostatic testosterone concentrations.1 3 9
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.
Importance of obtaining and reading patient information on dutasteride before initiation of therapy and with each new prescription refill.1
Importance of advising pregnant women or women who may become pregnant to avoid handling the drug.1 (See Pregnancy under Cautions.)
Advise patients that a decrease in the volume of ejaculate may occur but that this does not appear to interfere with normal sexual function.1
Advise patients of the small possibility of impotence and decreased libido.1 10
Advise patients of possibility of developing enlarged or tender breasts.1
Advise patients of possibility of allergic reactions (e.g., rash, pruritus, urticaria, swelling of lips or face).1
Advise patients that ≥6 months of therapy may be required before improvement in BPH symptoms occurs.2
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of advising patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules, liquid-filled | 0.5 mg | Avodart | GlaxoSmithKline |
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 07/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Avodart 0.5MG Capsules (GLAXO SMITH KLINE): 30/$129.98 or 90/$354.97
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 09, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
1. GlaxoSmithKline. Avodart (dutasteride) soft gelatin capsules prescribing information. Research Triangle Park, NC; 2005 May.
2. GlaxoSmithKline. Avodart (dutasteride) soft gelatin capsules patient information. Research Triangle Park, NC; Undated. Available at: . Accessed 2006 Aug 15.
3. Roehrborn CG, Boyle P, Nickel JC et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002 60:434-41.
4. Dull P, Reagan RW, Bahnson RR. Managing benign prostatic hyperplasia. Am Fam Physician. 2002; 66:77-84, 87-8. [IDIS 483339] [PubMed 12126034]
5. Roehrborn CG, McConnell JD, Lieber M et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retenion and need for surgery in men with clinical benign prostatic hyperplasia. PLESS study group. Urology. 1999; 53:473-80. [PubMed 10096369]
6. Potts JM. Prospective identification of National Institutes of Health category IV prostatitis in men with elevated prostate specific antigen. J Urol. 2000; 164:1550-3. [IDIS 455479] [PubMed 11025702]
7. de la Rossette JJ, Alivizatos G, Madersbacher S et al. EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol. 2001; 40:256-63. [PubMed 11684840]
8. Agency for Health Care Policy and Research. Benign prostatic hyperplasia: diagnosis and treatment. J Am Geriatric Soc. 1998; 46:1163-5.
9. Anon. Dutasteride (avodart) for benign prostatic hyperplasia. Med Lett Drugs Ther. 2002; 44:109-10. [PubMed 12500154]
10. GlaxoSmithKline. Research Triangle Park, NC: Personal communication.
11. American Urological Association. Guideline on the management of benign prostatic hyperplasia (BPH)(2003/updated 2006). Available at: . Accessed 2006 Aug 10.
Mar Plus may be available in the countries listed below.
Dexpanthenol is reported as an ingredient of Mar Plus in the following countries:
International Drug Name Search
In the US, Opana (oxymorphone systemic) is a member of the drug class narcotic analgesics and is used to treat Labor Pain and Pain.
US matches:
Oxymorphone hydrochloride (a derivative of Oxymorphone) is reported as an ingredient of Opana in the following countries:
International Drug Name Search
Atropine Methobromide may be available in the countries listed below.
Atropine Methobromide (BAN, JAN) is known as Atropine in the US.
International Drug Name Search
Glossary
| BAN | British Approved Name |
| JAN | Japanese Accepted Name |
Lorazépam Mylan may be available in the countries listed below.
Lorazepam is reported as an ingredient of Lorazépam Mylan in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
Amoxicillin trihydrate (a derivative of Amoxicillin) is reported as an ingredient of Robamox V in the following countries:
International Drug Name Search
Domperidon Mylan may be available in the countries listed below.
Domperidone maleate (a derivative of Domperidone) is reported as an ingredient of Domperidon Mylan in the following countries:
International Drug Name Search
Colipate may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Colistin sulfate (a derivative of Colistin) is reported as an ingredient of Colipate in the following countries:
International Drug Name Search
Cetirizin Sandoz may be available in the countries listed below.
Cetirizine dihydrochloride (a derivative of Cetirizine) is reported as an ingredient of Cetirizin Sandoz in the following countries:
International Drug Name Search
Generic Name: brompheniramine and pseudoephedrine (BROM fen EER a meen and SOO doe ed FED rin)
Brand Names: Andehist NR Syrup, Bidhist-D, Bromaline, Bromhist Pediatric Drops, Bromhist-NR, BroveX PD, BroveX PSE, Brovex SR, Di-Bromm, Histex SR, J-TanD PD, Lodrane 12D, Lodrane 24D, Lodrane D, Lodrane Liquid, LoHist-12D, LoHist-PD, Q-Tapp, Sildec, Touro Allergy, Ultrabrom, Ultrabrom PD
Brompheniramine 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 brompheniramine and pseudoephedrine 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.
Brompheniramine and pseudoephedrine may also be used for other purposes not listed in this medication guide.
There are many brands and forms of this medicine available and not all brands are listed on this leaflet.
Ask a doctor or pharmacist if it is safe for you to take brompheniramine and pseudoephedrine if you have:
diabetes;
glaucoma;
heart disease or high blood pressure;
diabetes;
a thyroid disorder;
an enlarged prostate; or
problems with urination.
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.
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.
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.
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.
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.
Overdose symptoms may include feeling restless or nervous, nausea, vomiting, stomach pain, dizziness, drowsiness, dry mouth, warmth or tingly feeling, or seizure (convulsions).
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.
fast, pounding, or uneven heartbeat;
confusion, hallucinations, unusual thoughts or behavior;
severe dizziness, anxiety, restless feeling, or nervousness;
increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure);
confusion, hallucinations, unusual thoughts or behavior;
easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms; or
urinating less than usual or not at all.
Less serious side effects may include:
blurred vision;
dry mouth;
nausea, stomach pain, constipation;
mild loss of appetite, stomach upset;
warmth, tingling, or redness under your skin;
sleep problems (insomnia);
restless or excitability (especially in children);
skin rash or itching;
dizziness, drowsiness;
problems with memory or concentration; or
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.
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;
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), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), 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 brompheniramine and pseudoephedrine. 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.
See also: Bromhist-NR side effects (in more detail)
Nafarelil may be available in the countries listed below.
Nafarelin acetate (a derivative of Nafarelin) is reported as an ingredient of Nafarelil in the following countries:
International Drug Name Search
Etasisen may be available in the countries listed below.
Aciclovir is reported as an ingredient of Etasisen in the following countries:
International Drug Name Search
Kafenac may be available in the countries listed below.
Aceclofenac is reported as an ingredient of Kafenac in the following countries:
International Drug Name Search
Cystografin is a brand name of diatrizoate, approved by the FDA in the following formulation(s):
No. There is currently no therapeutically equivalent version of Cystografin available.
Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Cystografin. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.
See also: About generic drugs.
There are no current U.S. patents associated with Cystografin.
Spersacarpin may be available in the countries listed below.
Pilocarpine hydrochloride (a derivative of Pilocarpine) is reported as an ingredient of Spersacarpin in the following countries:
International Drug Name Search
Isosorbide mononitraat EU-Pharma may be available in the countries listed below.
Isosorbide Mononitrate is reported as an ingredient of Isosorbide mononitraat EU-Pharma in the following countries:
International Drug Name Search
Clarazole may be available in the countries listed below.
Ketoconazole is reported as an ingredient of Clarazole in the following countries:
International Drug Name Search
Pencial may be available in the countries listed below.
Bicalutamide is reported as an ingredient of Pencial in the following countries:
International Drug Name Search
Clostilbegyt may be available in the countries listed below.
Clomifene citrate (a derivative of Clomifene) is reported as an ingredient of Clostilbegyt in the following countries:
International Drug Name Search
Formoterol Fumarate may be available in the countries listed below.
Formoterol Fumarate (BANM, USAN) is known as Formoterol in the US.
International Drug Name Search
Glossary
| BANM | British Approved Name (Modified) |
| USAN | United States Adopted Name |
Cloranfenicol Made may be available in the countries listed below.
Chloramphenicol is reported as an ingredient of Cloranfenicol Made in the following countries:
International Drug Name Search
RETROVIR (ZIDOVUDINE) HAS BEEN ASSOCIATED WITH HEMATOLOGIC TOXICITY, INCLUDING NEUTROPENIA AND SEVERE ANEMIA, PARTICULARLY IN PATIENTS WITH ADVANCED HUMAN IMMUNODEFICIENCY VIRUS (HIV) DISEASE (SEE WARNINGS). PROLONGED USE OF RETROVIR HAS BEEN ASSOCIATED WITH SYMPTOMATIC MYOPATHY.
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING RETROVIR AND OTHER ANTIRETROVIRALS (SEE WARNINGS).
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a pyrimidine nucleoside analogue active against HIV. RETROVIR IV Infusion is a sterile solution for intravenous infusion only. Each mL contains 10 mg zidovudine in Water for Injection. Hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH to approximately 5.5. RETROVIR IV Infusion contains no preservatives.
The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural formula:
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.
Activity of zidovudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC50 and EC90 values for zidovudine were 0.01 to 0.49 µM (1 μM = 0.27 mcg/mL) and 0.1 to 9 μM, respectively. HIV from therapy-naive subjects with no mutations associated with resistance gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 93 baseline samples from COLA40263) and 0.02 µM (0.01 to 0.03 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 μM, and against HIV-2 isolates from 0.00049 to 0.004 μM. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, and zalcitabine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.
Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of mutations. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.
In a study of 167 HIV-infected patients, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-associated mutations with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M mutation being most commonly associated with multi-drug resistance. The mutation at codon 151 in combination with mutations at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.
Adults: The pharmacokinetics of zidovudine have been evaluated in 22 adult HIV-infected patients in a Phase 1 dose-escalation study. Following intravenous (IV) dosing, dose-independent kinetics was observed over the range of 1 to 5 mg/kg. The major metabolite of zidovudine is 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV). GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 18% and 60%, respectively, following IV dosing. A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in the plasma following single-dose IV administration of zidovudine. The AMT AUC was one-fifth of the zidovudine AUC.
The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg/kg every 4 hours were 1.06 and 0.12 mcg/mL, respectively.
The zidovudine cerebrospinal fluid (CSF)/plasma concentration ratio was determined in 39 patients receiving chronic therapy with RETROVIR. The median ratio measured in 50 paired samples drawn 1 to 8 hours after the last dose of RETROVIR was 0.6.
| Parameter | Mean ± SD (except where noted) |
| Apparent volume of distribution (L/kg) | 1.6 ± 0.6 (n = 11) |
| Plasma protein binding (%) | <38 |
| CSF:plasma ratioa | 0.6 [0.04 to 2.62] (n = 39) |
| Systemic clearance (L/hr/kg) | 1.6 (0.8 to 2.7) (n =18) |
| Renal clearance (L/hr/kg) | 0.34 ± 0.05 (n = 16) |
| Elimination half-life (hr)b | 1.1 (0.5 to 2.9) (n = 19) |
| aMedian [range]. | |
| bApproximate range. | |
Adults With Impaired Renal Function: Zidovudine clearance was decreased resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal function (n = 14) following a single 200-mg oral dose (Table 2). Plasma concentrations of AMT were not determined. A dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥15 mL/min.
| Parameter | Control Subjects (Normal Renal Function) (n = 6) | Patients With Renal Impairment (n = 14) |
| CrCl (mL/min) | 120 ± 8 | 18 ± 2 |
| Zidovudine AUC (ng•hr/mL) | 1,400 ± 200 | 3,100 ± 300 |
| Zidovudine half-life (hr) | 1.0 ± 0.2 | 1.4 ± 0.1 |
| aData are expressed as mean ± standard deviation. | ||
The pharmacokinetics and tolerance of oral zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
Adults With Impaired Hepatic Function: Data describing the effect of hepatic impairment on the pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased and plasma concentrations would be increased following administration of the recommended adult doses to patients with hepatic impairment (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
Pediatrics: Zidovudine pharmacokinetics have been evaluated in HIV-infected pediatric patients (Table 3).
Patients Aged 3 Months to 12 Years: Overall, zidovudine pharmacokinetics in pediatric patients >3 months of age are similar to those in adult patients. Proportional increases in plasma zidovudine concentrations were observed following administration of oral solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV (see DOSAGE AND ADMINISTRATION: Pediatrics).
Patients Aged Less Than 3 Months: Zidovudine pharmacokinetics have been evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was determined immediately following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric patients >14 days old. For dose recommendations for neonates, see DOSAGE AND ADMINISTRATION: Neonatal Dosing.
| Parameter | Birth to 14 Days | Aged 14 Days to 3 Months | Aged 3 Months to 12 Years |
| Oral bioavailability (%) | 89 ± 19 (n = 15) | 61 ± 19 (n = 17) | 65 ± 24 (n = 18) |
| CSF:plasma ratio | no data | no data | 0.26 ± 0.17b (n = 28) |
| CL (L/hr/kg) | 0.65 ± 0.29 (n = 18) | 1.14 ± 0.24 (n = 16) | 1.85 ± 0.47 (n = 20) |
| Elimination half-life (hr) | 3.1 ± 1.2 (n = 21) | 1.9 ± 0.7 (n = 18) | 1.5 ± 0.7 (n = 21) |
| aData presented as mean ± standard deviation except where noted. | |||
| bCSF ratio determined at steady-state on constant intravenous infusion. | |||
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics. However, in another patient population, a potential for interaction has been identified (see PRECAUTIONS).
Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum (see PRECAUTIONS: Nursing Mothers).
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients over 65 years of age.
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no differences in zidovudine exposure (AUC) when a single dose of zidovudine was administered as the 300-mg RETROVIR Tablet.
See Table 4 and PRECAUTIONS: Drug Interactions.
Zidovudine Plus Lamivudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single oral dose of zidovudine (200 mg) in combination with multiple oral doses of lamivudine (300 mg every 12 hours).
| Coadministered Drug and Dose | Zidovudine Oral Dose | n | Zidovudine Concentrations | Concentration of Coadministered Drug | |
| AUC | Variability | ||||
Atovaquone 750 mg q 12 hr with food | 200 mg q 8 hr | 14 | ↑AUC 31% | Range 23% to 78%b | ↔ |
Fluconazole 400 mg daily | 200 mg q 8 hr | 12 | ↑AUC 74% | 95% CI: 54% to 98% | Not Reported |
Methadone 30 to 90 mg daily | 200 mg q 4 hr | 9 | ↑AUC 43% | Range 16% to 64%b | ↔ |
Nelfinavir 750 mg q 8 hr x 7 to 10 days | single 200 mg | 11 | ↓AUC 35% | Range 28% to 41% | ↔ |
Probenecid 500 mg q 6 hr x 2 days | 2 mg/kg q 8 hr x 3 days | 3 | ↑AUC 106% | Range 100% to 170%b | Not Assessed |
Rifampin 600 mg daily x 14 days | 200 mg q 8 hr x 14 days | 8 | ↓AUC 47% | 90% CI: 41% to 53% | Not Assessed |
Ritonavir 300 mg q 6 hr x 4 days | 200 mg q 8 hr x 4 days | 9 | ↓AUC 25% | 95% CI: 15% to 34% | ↔ |
Valproic acid 250 mg or 500 mg q 8 hr x 4 days | 100 mg q 8 hr x 4 days | 6 | ↑AUC 80% | Range 64% to 130%b | Not Assessed |
| ↑ = Increase; ↓ = Decrease;↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. | |||||
| aThis table is not all inclusive. | |||||
| bEstimated range of percent difference. | |||||
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/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/HCV co-infected patients (see WARNINGS).
RETROVIR IV Infusion in combination with other antiretroviral agents is indicated for the treatment of HIV infection.
RETROVIR is also indicated for the prevention of maternal-fetal HIV transmission as part of a regimen that includes oral RETROVIR beginning between 14 and 34 weeks of gestation, intravenous RETROVIR during labor, and administration of RETROVIR Syrup to the neonate after birth. The efficacy of this regimen for preventing HIV transmission in women who have received RETROVIR for a prolonged period before pregnancy has not been evaluated. The safety of RETROVIR for the mother or fetus during the first trimester of pregnancy has not been assessed (see Description of Clinical Studies).
Therapy with RETROVIR has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV disease at the initiation of therapy and to delay disease progression in asymptomatic HIV-infected patients.
RETROVIR in combination with other antiretroviral agents has been shown to be superior to monotherapy in one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA. The complete prescribing information for each drug should be consulted before combination therapy that includes RETROVIR is initiated.
Pregnant Women and Their Neonates: The utility of RETROVIR for the prevention of maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by intravenous administration of RETROVIR during labor and delivery. Following birth, neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically significant difference in the incidence of HIV infection in the neonates (based on viral culture from peripheral blood) between the group receiving RETROVIR and the group receiving placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV infection was 7.8% in the group receiving RETROVIR and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. RETROVIR was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.
RETROVIR IV Infusion is contraindicated for patients who have potentially life-threatening allergic reactions to any of the components of the formulation.
COMBIVIR® (lamivudine and zidovudine) Tablets and TRIZIVIR® (abacavir sulfate, lamivudine, and zidovudine) Tablets are combination product tablets that contain zidovudine as one of their components. RETROVIR should not be administered concomitantly with COMBIVIR or TRIZIVIR.
The incidence of adverse reactions appears to increase with disease progression; patients should be monitored carefully, especially as disease progression occurs.
RETROVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/dL. In patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant adverse events observed. There have been reports of pancytopenia associated with the use of RETROVIR, which was reversible in most instances, after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood transfusions, has occurred during treatment with RETROVIR alone or in combination with other antiretrovirals.
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage adjustments may be necessary (see DOSAGE AND ADMINISTRATION).
Myopathy and myositis with pathological changes, similar to that produced by HIV disease, have been associated with prolonged use of RETROVIR.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering RETROVIR to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with RETROVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions), hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and RETROVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of RETROVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh >6) (see the complete prescribing information for interferon and ribavirin).
Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver (glucuronidation). In patients with severely impaired renal function (CrCl<15 mL/min), dosage reduction is recommended. Although the data are limited, zidovudine concentrations appear to be increased in patients with severely impaired hepatic function, which may increase the risk of hematologic toxicity (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RETROVIR. 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 jirovecii 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.
RETROVIR is not a cure for HIV-1 infection, and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using RETROVIR.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
The safety and efficacy of RETROVIR in treating women, intravenous drug users, and racial minorities is not significantly different than that observed in white males.
Patients should be informed that the major toxicities of RETROVIR are neutropenia and/or anemia. The frequency and severity of these toxicities are greater in patients with more advanced disease and in those who initiate therapy later in the course of their infection. They should be told that if toxicity develops, they may require transfusions or drug discontinuation. They should be told of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced symptomatic HIV disease. They should be cautioned about the use of other medications, including ganciclovir and interferon alfa, which may exacerbate the toxicity of RETROVIR (see PRECAUTIONS: Drug Interactions). Patients should be informed that other adverse effects of RETROVIR include nausea and vomiting. Patients should also be encouraged to contact their physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being treated with RETROVIR.
Pregnant women considering the use of RETROVIR during pregnancy for prevention of HIV transmission to their infants should be advised that transmission may still occur in some cases despite therapy. The long-term consequences of in utero and neonatal exposure to RETROVIR are unknown, including the possible risk of cancer.
HIV-infected pregnant women should be advised not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected.
See CLINICAL PHARMACOLOGY section (Table 4) for information on zidovudine concentrations when coadministered with other drugs. For patients experiencing pronounced anemia or other severe zidovudine-associated events while receiving chronic administration of zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4, zidovudine dose reduction may be considered.
Antiretroviral Agents: Concomitant use of zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro.
Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of RETROVIR against HIV; concomitant use of such drugs should be avoided.
Doxorubicin: Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro (see CLINICAL PHARMACOLOGY for additional drug interactions).
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving RETROVIR, while in 1 case a high level was documented. However, in a pharmacokinetic interaction study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.
Overlapping Toxicities: Coadministration of ganciclovir, interferon alfa, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg/kg/day in mice and 80, 220, and 600 mg/kg/day in rats. The doses in mice were reduced to 20, 30, and 40 mg/kg/day after day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg/kg/day on day 91, and then to 300 mg/kg/day on day 279.
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.
Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine employed in this study produced zidovudine exposures approximately 3 times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (∼1,000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine. It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates.
Pregnancy Category C. Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 mg/kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated area under the curve [AUC] in rats at this dose level was 300 times the daily AUC in humans given 600 mg per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.
Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis, Mutagenesis, Impairment of Fertility).
A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV transmission (see INDICATIONS AND USAGE: Description of Clinical Studies). Congenital abnormalities occurred with similar frequency between neonates born to mothers who received RETROVIR and neonates born to mothers who received placebo. Abnormalities were either problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
Zidovudine is excreted in human milk (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Nursing Mothers). Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving RETROVIR (see Pediatric Use and INDICATIONS AND USAGE: Maternal-Fetal HIV Transmission).
RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age who had HIV-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-related immunosuppression. RETROVIR has also been studied in neonates perinatally exposed to HIV (see ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, INDICATIONS AND USAGE: Description of Clinical Studies, and CLINICAL PHARMACOLOGY: Pharmacokinetics).
Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
The adverse events reported during intravenous administration of RETROVIR IV Infusion are similar to those reported with oral administration; neutropenia and anemia were reported most frequently. Long-term intravenous administration beyond 2 to 4 weeks has not been studied in adults and may enhance hematologic adverse events. Local reaction, pain, and slight irritation during intravenous administration occur infrequently.
The frequency and severity of adverse events associated with the use of RETROVIR are greater in patients with more advanced infection at the time of initiation of therapy.
Table 5 summarizes events reported at a statistically significantly greater incidence for patients receiving RETROVIR orally in a monotherapy study:
| Adverse Event | RETROVIR 500 mg/day (n = 453) | Placebo (n = 428) |
| Body as a whole | ||
| Asthenia | 8.6%b | 5.8% |
| Headache | 62.5% | 52.6% |
| Malaise | 53.2% | 44.9% |
| Gastrointestinal | ||
| Anorexia | 20.1% | 10.5% |
| Constipation | 6.4%b | 3.5% |
| Nausea | 51.4% | 29.9% |
| Vomiting | 17.2% | 9.8% |
| aReported in ≥5% of study population. | ||
| bNot statistically significant versus placebo. | ||
In addition to the adverse events listed in Table 5, other adverse events observed in clinical studies were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, hyperbilirubinemia, insomnia, musculoskeletal pain, myalgia, and neuropathy.
Selected laboratory abnormalities observed during a clinical study of monotherapy with oral RETROVIR are shown in Table 6.
| Adverse Event | RETROVIR 500 mg/day (n = 453) | Placebo (n = 428) |
| Anemia (Hgb<8 g/dL) | 1.1% | 0.2% |
| Granulocytopenia (<750 cells/mm3) | 1.8% | 1.6% |
| Thrombocytopenia (platelets<50,000/mm3) | 0% | 0.5% |
| ALT (>5 x ULN) | 3.1% | 2.6% |
| AST (>5 x ULN) |
