SEO Content Directory Saba: September 2016

Thursday, September 29, 2016

Pilocarpine Hydrochloride

Class: Miotics
VA Class: OP102
CAS Number: 92-13-7
Brands: Isopto Carpine, Pilopine HS

Introduction

Miotic; direct-acting parasympathomimetic agent.^a ^c ^d ^e

Uses for Pilocarpine Hydrochloride

Open-angle Glaucoma

Reduction of elevated intraocular pressure (IOP)^c ^d ^e in patients with primary open-angle (chronic simple, noncongestive) glaucoma.^b

May use concomitantly with other miotics, sympathomimetic agents, β-adrenergic blocking agents, carbonic anhydrase inhibitors, or hyperosmotic agents.^c ^d ^e

Angle-closure Glaucoma

Reduction of IOP in the emergency treatment of acute (congestive) angle-closure glaucoma prior to surgery.^b Because it may preclude successful surgery, do not use for long periods prior to surgical treatment.^b

Lack of response may be caused by paralysis of the iris sphincter by the extremely high IOP; systemic administration of acetazolamide or hyperosmotic solutions (e.g., glycerin or mannitol) may be required.^b

Ocular Surgery

Reduction of IOP and protection of the lens by causing miosis prior to goniotomy or iridectomy, including laser iridectomy.^b

May use to control glaucoma which persists after surgery.^b

Ophthalmologic Examinations

Production of miosis to counteract mydriatic effects of sympathomimetic agents (e.g., phenylephrine) after ophthalmoscopic examinations in glaucoma patients.^b

Pilocarpine Hydrochloride Dosage and Administration

Administration

Ophthalmic Administration

Avoid contamination of the solution or gel container.^c ^d ^e

Ophthalmic solutions are preferred when an acute reduction in IOP and/or an intense miotic effect are necessary (e.g., prior to surgery, following ophthalmologic examinations).^a

Tonometric measurements recommended before and during therapy.^a

Ophthalmic Solution

Apply topically to the conjunctival sac of affected eye(s) as directed by clinician, usually 3–4 times daily; more frequent administration may be necessary in some patients.^a ^c ^e Not for injection.^c ^e

Following topical instillation, apply finger pressure on the lacrimal sac for 1–2 minutes to minimize drainage into nose and throat and reduce risk of absorption and systemic reactions.^a Remove excess solution around the eye with a tissue and rinse off any medication on hands immediately.^a

Ophthalmic Gel

Apply topically to the lower conjunctival sac of affected eye(s) once daily at bedtime.^d

Measure IOP just before next dose following initiation of therapy to ensure adequate control of IOP throughout the 24-hour dosing interval.^a

If used concomitantly with ophthalmic solutions, instill solutions first and apply gel ≥5 minutes later.^a

Dosage

Available as pilocarpine hydrochloride; dosage expressed in terms of the salt.^a

Adjust concentration and frequency of solution instillation according to patient requirements and response, as determined by tonometric readings.^a

In patients with heavily pigmented irides, higher solution concentrations may be required.^c ^e

Adjust dosage of ophthalmic gel based on periodic tonometric readings.^a

Adults

Open-Angle Glaucoma

Ophthalmic

1–2 drops of a 1–4% solution in the eye(s) every 4–12 hours.^a Solution concentrations >4% are only occasionally more effective than lower concentrations.^a

Apply a 1.3-cm (0.5-inch) ribbon of a 4% gel into lower conjunctival sac once daily at bedtime.^d

Acute Angle-Closure Glaucoma

Ophthalmic

1 drop of a 2% solution in the affected eye every 5–10 minutes for 3–6 doses, followed by 1 drop every 1–3 hours until pressure is controlled.^a To prevent a bilateral attack, 1 drop of a 1–2% solution in the unaffected eye every 6–8 hours.^a

Ocular Surgery

Iridectomy

Ophthalmic

1 drop of a 2% solution 4 times immediately prior to iridectomy has been used.^a

Congenital Glaucoma (Goniotomy)

Ophthalmic

1 drop of a 2% solution every 6 hours prior to surgery has been used.^a

May use a 2% solution to fill the gonioscopic lens prior to goniotomy, or may administer 1 drop of a 2% solution every 6 hours plus 3 times in the 30 minutes immediately preceding goniotomy, with or without concomitant administration of acetazolamide.^a

Ophthalmologic Examinations

Ophthalmic

1 drop of a 1% solution in the affected eye(s).^a

Cautions for Pilocarpine Hydrochloride

Contraindications

Known hypersensitivity to pilocarpine or any ingredient in the formulation.^c ^d ^e

Conditions in which pupillary constriction is undesirable (e.g., acute iritis, pupillary block).^c ^d ^e

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Allergic conjunctivitis, dermatitis, or keratitis reported occasionally with miotics; these reactions are usually alleviated by changing to another miotic.^b In some instances, allergic reactions may be caused by preservatives in the preparations.^b

General Precautions

Ocular Effects

Retinal detachment reported rarely;^c ^d ^e use with extreme caution, if at all, in patients with a history or risk of retinal detachment, especially those who are young or aphakic.^b Carefully examine retinal periphery at least annually to detect an impending detachment.^b

Use with caution in patients with corneal abrasion to avoid excessive penetration and systemic toxicity.^b

Possible spasm of accommodation and poor vision in dim light, particularly in geriatric patients and patients with lens opacities.^c ^d ^e (See Advice to Patients.)

Follicular conjunctival hypertrophy may occur with prolonged therapy.^b

Possible transient increase in IOP even when the angle is open.^b ^e In some patients with angle-closure glaucoma receiving miotics, IOP may be increased and acute attacks may be precipitated.^b

Possible corneal opacities.^c ^d

Regular slit-lamp examinations recommended; discontinue therapy, at least temporarily, if iris cysts, iritis, synechiae, or lens opacities occur.^b

Specific Populations

Pregnancy

Category C.^c

Lactation

Not known whether pilocarpine is distributed into milk.^c ^d ^e Use with caution.^c ^d ^e

Pediatric Use

Safety and efficacy not established.^d ^e

Geriatric Use

Reduced visual acuity in dim light frequently experienced in geriatric patients.^d ^e

Common Adverse Effects

Ocular irritation (burning or discomfort), lacrimation, temporal or periorbital headache, painful ciliary or accommodative spasm, blurred vision or myopia, conjunctival vascular congestion, superficial keratitis, poor vision in dim light.^a ^b ^c ^d ^e

Interactions for Pilocarpine Hydrochloride

Specific Drugs

Drug	Interaction	Comments
Ocular hypotensive agents	Additive IOP lowering effects^b	Used to therapeutic advantage^b
Anticholinesterase miotics	Competitive inhibition of miotic effect and presumably IOP-lowering effect^b	Concomitant administration generally not recommended^b Some clinicians recommend administration of pilocarpine at onset of long-acting anticholinesterase therapy followed by gradual taper of pilocarpine so that antagonism between the drugs allows full effects of the anticholinesterase to be obtained gradually^b

Pilocarpine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Penetrates cornea rapidly.^b Application of ophthalmic gel results in increased corneal bioavailability secondary to decreased elimination of pilocarpine from precorneal areas compared with a topically applied solution.^a IOP reduction and pupillary diameter are similar to values obtained following application of a solution.^a

Onset

Following topical application of a 1% solution to the conjunctival sac, miosis occurs within 10–30 minutes and is maximal within 30 minutes.^a Reduction in IOP is detectable within 60 minutes and is maximal within 75 minutes.^a Spasms of accommodation begin in approximately 15 minutes.^a

Duration

Following topical application of a 1% solution to the conjunctival sac, miosis usually persists 4–8 hours or rarely up to 20 hours.^a Reduced IOP persists 4–14 hours, depending on concentration of drug used.^a Spasms of accommodation persist 2–3 hours.^a

Application of ophthalmic gel results in an increased duration of ocular effects compared with a topically applied solution.^a Following topical application of gel, IOP decreases for about 18–24 hours after application.^a

Distribution

Extent

Bound to serum and ocular tissues.^b

Not known whether pilocarpine is distributed into milk.^c ^d ^e

Elimination

Metabolism

Mechanism by which pilocarpine is inactivated in the body is unclear.^b

Stability

Storage

Ophthalmic

Solution

8–27°C,^c unless otherwise specified by manufacturer.

Gel

2–27°C.^d Avoid excessive heat; do not freeze.^d

ActionsActions

Directly stimulates cholinergic receptors, resulting in muscarinic and nicotinic effects.^b ^c

Contracts the iris sphincter and the ciliary muscle, which produces constriction of the pupil (miosis) and spasm of accommodation, respectively.^b ^c ^e

Reduces IOP in normal and glaucomatous eyes.^b ^c

Facilitates aqueous humor outflow by contracting the ciliary muscle and widening the trabecular meshwork.^b ^c

Decreases activity of extraocular muscles of convergence and causes vasodilation of blood vessels of the conjunctiva, iris, and ciliary body and increased permeability of the blood-aqueous barrier, which may lead to vascular congestion and ocular inflammation.^b

Advice to Patients

Importance of learning and adhering to proper administration techniques to avoid contamination of the solution or gel container.^b

Importance of removing soft contact lenses before administration (since pilocarpine may be absorbed by or preservatives in preparations may have a deleterious effect on the lenses).^b

Caution advised if driving at night or performing hazardous tasks in dim light.^c ^d ^e

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^b

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

Importance of informing patients of other precautionary information.^a (See Cautions.)

Preparations

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

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Pilocarpine Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Bulk	Powder
Ophthalmic	Gel	4%	Pilopine HS (with benzalkonium chloride and edetate disodium)	Alcon
	Solution	0.5%*	Pilocarpine Hydrochloride Ophthalmic Solution	Bausch & Lomb
		1%*	Isopto Carpine (with benzalkonium chloride)	Alcon
			Pilocarpine Hydrochloride Ophthalmic Solution	Akorn, Bausch & Lomb, Falcon
		2%*	Isopto Carpine (with benzalkonium chloride)	Alcon
			Pilocarpine Hydrochloride Ophthalmic Solution	Akorn, Bausch & Lomb, Falcon
		3%*	Pilocarpine Hydrochloride Ophthalmic Solution	Bausch & Lomb
		4%*	Isopto Carpine (with benzalkonium chloride)	Alcon
			Pilocarpine Hydrochloride Ophthalmic Solution	Akorn, Bausch & Lomb, Falcon
		6%*	Pilocarpine Hydrochloride Ophthalmic Solution	Bausch & Lomb, Falcon

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Isopto Carpine 1% Solution (ALCON VISION): 15/$36.99 or 45/$100.97

Isopto Carpine 2% Solution (ALCON VISION): 15/$36.99 or 45/$103.97

Pilocarpine HCl 1% Solution (FALCON PHARMACEUTICALS): 15/$37.99 or 30/$66.97

Pilocarpine HCl 2% Solution (FALCON PHARMACEUTICALS): 15/$37.99 or 30/$68.97

Pilopine HS 4% Gel (ALCON VISION): 4/$79.99 or 12/$225.97

Disclaimer

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

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

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

a. AHFS Drug Information 2003. McEvoy GK, ed. Pilocarpine. Bethesda, MD: American Society of Health-System Pharmacists; 2003:2679-82.

b. AHFS Drug Information 2003. McEvoy GK, ed. Miotics General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2003:2674-77.

c. Falcon. Pilocarpine hydrochloride 1%, 2%, 4%, or 6% Ophthalmic Solution prescribing information. Fort Worth, TX; 2003 Aug.

d. Alcon. Pilopine HS (pilocarpine hydrochloride) 4% Ophthalmic Gel prescribing information. Fort Worth, TX; 1999 Mar.

e. Alcon. Isopto Carpine (pilocarpine hydrochloride) ophthalmic solution prescribing information. Fort Worth, TX; 2003 Oct.

More Pilocarpine Hydrochloride resources

Pilocarpine Hydrochloride Use in Pregnancy & Breastfeeding
Pilocarpine Hydrochloride Drug Interactions
Pilocarpine Hydrochloride Support Group
0 Reviews for Pilocarpine Hydrochloride - Add your own review/rating

Pilocarpine Prescribing Information (FDA)

Pilocarpine Professional Patient Advice (Wolters Kluwer)

pilocarpine Concise Consumer Information (Cerner Multum)

Pilocarpine MedFacts Consumer Leaflet (Wolters Kluwer)

pilocarpine Advanced Consumer (Micromedex) - Includes Dosage Information

Salagen Prescribing Information (FDA)

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Dronedarone hydrochloride

Dronedarone hydrochloride may be available in the countries listed below.

Ingredient matches for Dronedarone hydrochloride

Dronedarone

Dronedarone hydrochloride (USAN) is known as Dronedarone in the US.

International Drug Name Search

Glossary

USAN

United States Adopted Name

Click for further information on drug naming conventions and International Nonproprietary Names.

Zodryl AC 35

Generic Name: chlorpheniramine and codeine (KLOR fen IR a meed and KOE deen)

Brand Names: Cotab A, Cotab AX, Notuss-AC, Z-Tuss AC, Zodryl AC 25, Zodryl AC 30, Zodryl AC 35, Zodryl AC 40, Zodryl AC 50, Zodryl AC 60, Zodryl AC 80

What is Zodryl AC 35 (chlorpheniramine and codeine)?

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

Codeine is a narcotic cough suppressant. It affects the signals in the brain that trigger cough reflex.

The combination of chlorpheniramine and codeine is used to treat runny or stuffy nose, sneezing, watery eyes, and cough caused by allergies or the common cold.

Chlorpheniramine and codeine will not treat a cough that is caused by smoking, asthma, or emphysema.

Chlorpheniramine and codeine may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Zodryl AC 35 (chlorpheniramine and codeine)?

Do not take a cough and cold if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take a cough and cold medicine before the MAO inhibitor has cleared from your body. You should not take this medication if you are allergic to chlorpheniramine or codeine, or if you have severe high blood pressure or coronary artery disease, ischemic heart disease, a stomach ulcer, narrow-angle glaucoma, if you are having an asthma attack, if you are pregnant or breast-feeding, or if you are unable to urinate.

Before taking this medication, tell your doctor if you have asthma or other breathing disorder, glaucoma, heart disease, high blood pressure, seizures, a thyroid disorder, diabetes, urination problems, stomach problems, liver or kidney disease, Addison's disease, mental illness, or a history of drug or alcohol addiction.

Codeine may be habit-forming and should be used only by the person it was prescribed for. This medication should never be shared with another person, especially someone who has a history of drug abuse or addiction. Keep the medication in a secure place where others cannot get to it. Do not give this medicine to a child younger than 6 years old.

What should I discuss with my healthcare provider before taking Zodryl AC 35 (chlorpheniramine and codeine)?

severe or uncontrolled high blood pressure;

severe coronary artery disease;

ischemic heart disease;

a stomach ulcer;

narrow-angle glaucoma;

if you are having an asthma attack;

if you are unable to urinate; or

if you are pregnant or breast-feeding.

If you have any of these other conditions, you may need a dose adjustment or special tests to safely use this medication:

asthma, COPD, emphysema, or other breathing disorder;

glaucoma;

heart disease, high blood pressure;

a history of head injury or brain tumor;

epilepsy or other seizure disorder;

a thyroid disorder;

diabetes;

enlarged prostate or urination problems;

stomach or intestinal problems;

liver or kidney disease;

Addison's disease;

mental illness; or

a history of drug or alcohol addiction.

FDA pregnancy category C. It is not known whether chlorpheniramine and codeine is harmful to an unborn baby. Codeine can cause breathing problems or addiction/withdrawal symptoms in a newborn. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Codeine can pass into breast milk and may harm a nursing baby. The use of codeine by some nursing mothers may lead to life-threatening side effects in the baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Older adults are more likely to have side effects from this medicine.

Do not give chlorpheniramine and codeine to a child younger than 6 years old. Codeine may be habit-forming and should be used only by the person it was prescribed for. This medication should never be shared with another person, especially someone who has a history of drug abuse or addiction. Keep the medication in a secure place where others cannot get to it.

How should I take Zodryl AC 35 (chlorpheniramine and codeine)?

Take this medication exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Do not take this medication more often than you doctor has prescribed. An overdose of chlorpheniramine and codeine can cause life-threatening side effects. Take chlorpheniramine and codeine with a full glass of water.

Measure liquid 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.

Chlorpheniramine and codeine can be taken with food if it upsets your stomach.

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

Store chlorpheniramine and codeine at room temperature away from moisture and heat. Keep track of how much of this medicine has been used from each new bottle. Codeine is a drug of abuse and you should be aware if any person in the household is using this medicine improperly or without a prescription.

What happens if I miss a dose?

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

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An overdose of chlorpheniramine and codeine can be fatal, especially to a child.

Overdose symptoms may include feeling restless or nervous, sleep problems, extreme drowsiness, weak or limp feeling, confusion, hallucinations, chest pain, shortness of breath, uneven heartbeats, pinpoint pupils, cold and clammy skin, fainting, seizure (convulsions), weak pulse, shallow breathing, or breathing that stops.

What should I avoid while taking Zodryl AC 35 (chlorpheniramine and codeine)?

This medication can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid drinking alcohol while using chlorpheniramine and codeine. Alcohol may increase drowsiness and dizziness.

Zodryl AC 35 (chlorpheniramine and codeine) side effects

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

weak or shallow breathing;

chest tightness, fast heart rate;

painful urination;

urinating less than usual or not at all; or

confusion, hallucinations, or unusual behavior.

Less serious side effects may include:

feeling restless or excited (especially in children);

dizziness, drowsiness, loss of coordination;

ringing in your ears;

constipation or diarrhea;

nausea, vomiting, loss of appetite;

dry mouth, nose, or throat; or

mild itching or skin rash.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Zodryl AC 35 (chlorpheniramine and codeine)?

Narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by chlorpheniramine and codeine. Tell your doctor if you regularly use any of these medicines, or any other cold or allergy medicine.

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

atropine (Donnatal, and others), benztropine (Cogentin), dimenhydrinate (Dramamine), methscopolamine (Pamine), or scopolamine (Transderm-Scop);

bronchodilators such as ipratroprium (Atrovent) or tiotropium (Spiriva);

glycopyrrolate (Robinul);

mepenzolate (Cantil);

bladder or urinary medications such as darifenacin (Enablex), flavoxate (Urispas), oxybutynin (Ditropan, Oxytrol), tolterodine (Detrol), or solifenacin (Vesicare);

irritable bowel medications such as dicyclomine (Bentyl), hyoscyamine (Anaspaz, Cystospaz, Levsin, and others), or propantheline (Pro-Banthine); or

an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate).

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

More Zodryl AC 35 resources

Zodryl AC 35 Side Effects (in more detail)
Zodryl AC 35 Use in Pregnancy & Breastfeeding
Zodryl AC 35 Drug Interactions
Zodryl AC 35 Support Group
0 Reviews for Zodryl AC 35 - Add your own review/rating

Codeprex Prescribing Information (FDA)

Codeprex Consumer Overview

Cotab A MedFacts Consumer Leaflet (Wolters Kluwer)

EndaCof-C Prescribing Information (FDA)

Notuss-AC Liquid MedFacts Consumer Leaflet (Wolters Kluwer)

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Where can I get more information?

Your pharmacist can provide more information about chlorpheniramine and codeine.

See also: Zodryl AC 35 side effects (in more detail)

Tinidazole

Class: Antiprotozoals, Miscellaneous
VA Class: AP109
Chemical Name: 1-[2-(Ethylsulfonyl)ethyl]-2-methyl-5-nitro-1H-imidazole
Molecular Formula: C₈H₁₃N₃O₄S
CAS Number: 19387-91-8
Brands: Tindamax

Metronidazole (a nitroimidazole anti-infective chemically similar to tinidazole) is carcinogenic in mice and rats.¹ ³¹

Carcinogenic potential of tinidazole not evaluated in animal studies to date.¹

Avoid unnecessary use; reserve for use in approved indications.¹ (See Uses.)

Introduction

Antiprotozoal and antibacterial; ¹ ⁵⁸ ⁵⁹ ⁶³ ⁶⁴ ⁶⁵ ⁶⁸ nitroimidazole derivative.¹ ⁵⁸ ⁵⁹ ⁶³ ⁶⁴ ⁶⁵ ⁶⁸

Uses for Tinidazole

Amebiasis

Treatment of intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica in adults and children >3 years of age.¹ ¹⁸ ²⁵ ²⁶ ²⁷ ²⁸ ²⁹ ³⁰ ³⁴ ⁴³ ⁴⁷ ⁴⁸ ⁴⁹ ⁵⁰ ⁵¹ ⁵² ⁵³ ⁵⁴ ⁶⁹ Designated an orphan drug by FDA for treatment of amebiasis.²

Oral tinidazole or oral metronidazole followed by a luminal amebicide (iodoquinol, paromomycin) is the regimen of choice for mild to moderate or severe intestinal disease and for amebic hepatic abscess.¹⁸ ²⁴ ²⁵ ²⁶ ²⁷ ³⁴ ⁴⁷

Not recommended for treatment of asymptomatic cyst passers;¹ ¹⁸ ⁴⁷ these patients should be treated with a luminal amebicide such as iodoquinol, paromomycin, or diloxanide furoate (not commercially available in the US).¹⁸ ²⁵ ²⁶ ²⁷

Giardiasis

Treatment of giardiasis caused by Giardia duodenalis (also known as G. lamblia or G. intestinalis) in adults and children >3 years of age.¹ ¹⁸ ²⁰ ²¹ ²² ²³ ²⁴ ³⁴ ⁴⁰ ⁴¹ ⁴³ ⁴⁴ ⁴⁵ ⁴⁶ ⁵⁶ ⁵⁷ Designated an orphan drug by FDA for use in this condition.²

Drugs of choice are metronidazole,¹⁷ ¹⁸ ²⁰ tinidazole,¹⁷ ¹⁸ ²⁰ or nitazoxanide;¹⁷ ¹⁸ alternatives are paromomycin (especially in pregnant women),¹⁷ ¹⁸ ²⁰ furazolidone (not commercially available in the US),¹⁷ ¹⁸ ²⁰ or quinacrine (not commercially available in the US).¹⁷ ¹⁸

Treatment of asymptomatic carriers of giardiasis† not recommended, except possibly to prevent transmission from carriers in households of patients with hypogammaglobulinemia or cystic fibrosis or pregnant women with toddlers.¹⁸

Trichomoniasis

Treatment of symptomatic and asymptomatic trichomoniasis in men and women in whom Trichomonas vaginalis has been demonstrated by an appropriate diagnostic procedure (e.g., wet smear and/or culture, OSOM Trichomonas Rapid Test, Affirm VP III).¹ ³ ⁴ ⁵ ⁹ ¹¹ ¹³ ¹⁴ ¹⁵ ¹⁶ ¹⁸ ³⁵ ³⁶ ³⁸ ³⁹ ⁶⁷ ⁶⁸

Drug of choice is metronidazole or tinidazole.⁹ ¹⁷ ¹⁸ Tinidazole may be effective in some patients who do not respond to metronidazole,³ ⁶² but some T. vaginalis isolates with reduced susceptibility to metronidazole may also have reduced susceptibility to tinidazole.¹ ⁶¹ ⁶²

Goal of treatment is to provide symptomatic relief, achieve microbiologic cure, and reduce transmission.¹ ⁷ ⁸ ⁹ ¹⁵ To achieve this goal, both the index patient and sexual (particularly steady) partner(s) should be treated simultaneously;¹ ⁷ ⁸ ⁹ ¹⁵ treat sexual contacts presumptively even if they are asymptomatic and/or T. vaginalis has not been demonstrated.⁶⁷

Bacterial Vaginosis

Treatment of bacterial vaginosis (formerly called Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis) in nonpregnant women.¹ ⁷² ⁷³ Rule out other pathogens commonly associated with vulvovaginitis (e.g., Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans, herpes simplex viruses).¹

CDC recommends treatment of bacterial vaginosis in all symptomatic nonpregnant women.⁹ Routine treatment of sex partners not recommended.⁹

Nongonococcal Urethritis

Treatment of recurrent and persistent urethritis† in patients with nongonococcal urethritis who have already been treated with a recommended regimen.⁹

For treatment of nongonococcal urethritis in adults, CDC recommends a single oral dose of azithromycin or a 7-day regimen of doxycycline; alternative regimens are a 7-day regimen of oral erythromycin base or ethylsuccinate or a 7-day regimen of oral ofloxacin or oral levofloxacin.⁹ Patients are instructed to abstain from sexual intercourse until 7 days after initiation of treatment and to return for evaluation if symptoms persist or recur after completion of therapy; symptoms alone (without documentation of signs or laboratory evidence of urethral inflammation) are not sufficient basis for retreatment.⁹

Patients with persistent or recurrent urethritis who were not compliant with the treatment regimen or were reexposed to untreated sexual partner(s) should be retreated with the initial regimen.⁹ If patient with recurrent and persistent urethritis was compliant with the regimen and reexposure can be excluded, CDC recommends a single oral dose of metronidazole or tinidazole given in conjunction with a single oral dose of azithromycin (if azithromycin was not used in the initial regimen).⁹

Tinidazole Dosage and Administration

Administration

Oral Administration

Administer orally once daily with food.¹

Administration with meals may reduce incidence of adverse GI effects.¹

Do not consume alcohol during or for 3 days after completion of tinidazole therapy.¹

For children and other patients unable to swallow tablets, an oral suspension may be prepared extemporaneously using the tablets.¹

Extemporaneous Oral Suspension

To prepare an oral suspension containing 66.7 mg/mL, grind 2 g (four 500-mg tablets) to a fine powder with a mortar and pestle.¹ Add approximately 10 mL of cherry syrup to the powder and mix until smooth.¹ Transfer suspension to a graduated amber container;¹ use several small rinses of the cherry syrup to transfer any remaining drug in the mortar to provide a suspension with a final volume of 30 mL.¹

Shake suspension well prior to administration of each dose.¹

Dosage

Pediatric Patients

Amebiasis

Entamoeba histolytica Infections

Oral

Children >3 years of age (intestinal amebiasis): 50 mg/kg (up to 2 g) once daily given for 3 days;¹ ¹⁷ follow-up with an oral luminal amebicide (e.g., iodoquinol, paromomycin).¹ ¹⁸ ²⁵ ⁴⁷

Children >3 years of age (amebic liver abscess): 50 mg/kg (up to 2 g) once daily given for 3–5 days;¹ ¹⁷ follow-up with an oral luminal amebicide (e.g., iodoquinol, paromomycin).¹ ¹⁸ ²⁵ ⁴⁷

Giardiasis

Oral

Children >3 years of age: 50 mg/kg (up to 2 g) given as a single dose.¹ ¹⁷

Trichomoniasis†

Oral

Children >3 years of age†: 50 mg/kg (up to 2 g) given as a single dose.¹⁷

Adults

Amebiasis

Entamoeba histolytic Infections

Oral

Intestinal amebiasis: 2 g once daily given for 3 days;¹ ¹⁷ follow-up with an oral luminal amebicide (e.g., iodoquinol, paromomycin).¹ ¹⁸ ²⁵ ⁴⁷

Amebic liver abscess: 2 g once daily for 3–5 days;¹ ¹⁷ follow-up with an oral luminal amebicide (e.g., iodoquinol, paromomycin).¹ ¹⁸ ²⁵ ⁴⁷

Giardiasis

Oral

2 g given as a single dose.¹ ¹⁷

Trichomoniasis

Oral

2 g given as a single dose.¹ ⁹ ¹⁷

Treat sexual partners of the patient simultaneously using the same dosage.¹ ⁹ ⁶⁷

For treatment failure following a metronidazole regimen (e.g., single 2-g dose of metronidazole), CDC recommends retreatment with a single 2-g dose of tinidazole; if retreatment fails, CDC recommends tinidazole 2 g once daily for 5 days.⁹ If multiple-dose regimen fails, consult a specialist.⁹

Bacterial Vaginosis

Nonpregnant Women

Oral

2 g once daily for 2 days or 1 g once daily for 5 days.¹

Nongonococcal Urethritis†

Oral

CDC recommends a single 2-g dose of tinidazole in conjunction with a single1-g dose of oral azithromycin (if azithromycin not used in the initial regimen) for treatment of recurrent and persistent urethritis in patients who previously received a recommended regimen. (See Nongonococcal Urethritis under Uses.)⁹

Prescribing Limits

Pediatric Patients

Oral

Children >3 years of age: Maximum 50 mg/kg (up to 2 g) daily or as a single dose.¹ ¹⁷

Special Populations

Hepatic Impairment

Data insufficient to make specific dosage recommendations.¹ Use usual dosage with caution.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustments not needed, unless patient is undergoing hemodialysis.¹ ⁶⁰

If given on a day that hemodialysis is performed, administer an additional dose (equivalent to 50% of the recommended dose) after the dialysis session.¹ ⁶⁰

Geriatric Patients

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

Cautions for Tinidazole

Contraindications

History of hypersensitivity reaction to tinidazole or other nitroimidazole derivatives.¹

First trimester of pregnancy.¹

Breast-feeding.¹ (See Lactation under Cautions.)

Warnings/Precautions

Warnings

Carcinogenicity

Carcinogenic effects reported in mice and rats following chronic oral administration of metronidazole (a chemically related nitroimidazole anti-infective).¹ ³¹ (See Boxed Warning). Similar animal studies using tinidazole have not been reported to date.¹

Because of potential risks, tinidazole should be reserved for approved indications only and unnecessary use avoided.¹

Nervous System Effects

Convulsive seizures and peripheral neuropathy (characterized by numbness or paresthesia of an extremity) reported with tinidazole and other nitroimidazoles (e.g., metronidazole).¹ ³¹

If abnormal neurologic signs develop, promptly discontinue drug.¹

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., urticaria, pruritus, rash, flushing, sweating, dryness of mouth, fever, burning sensation, thirst, salivation, angioedema, bronchospasm, dyspnea, Stevens-Johnson syndrome, erythema multiforme) reported.¹ ⁵⁵

General Precautions

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of tinidazole and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.¹

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.¹ In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.¹

History of Blood Dyscrasia

Use with caution in patients with evidence or history of blood dyscrasia.¹ ⁵⁸

As with other nitroimidazoles (e.g., metronidazole), transient leukopenia and neutropenia may occur; persistent hematologic abnormalities not reported to date.¹ ³¹ ⁵⁸

If retreatment is necessary, perform total and differential leukocyte counts.¹

Candidiasis

Vaginal candidiasis reported; treat with an appropriate antifungal.¹

Specific Populations

Pregnancy

Category C (second and third trimesters).¹

Contraindicated during first trimester.¹

Not evaluated for treatment of bacterial vaginosis in pregnant women.¹

Lactation

Distributed into milk in concentrations similar to serum concentrations.¹ ⁶⁶ Interrupt breast-feeding during therapy and for 72 hours following the last dose.¹ ⁶⁶

Pediatric Use

Safety and efficacy not established in pediatric patients ≤3 years of age.¹ Some data available regarding safety and efficacy for treatment of giardiasis in pediatric patients <3 years of age†.¹⁸ ²³ ³² ⁴² ⁴³ ⁴⁴ ⁵⁷

Safety and efficacy in pediatric patients >3 years of age established only for treatment of amebiasis or giardiasis.¹ ¹⁸

Monitor pediatric patients closely if duration of therapy is >3 days (e.g., for treatment of amebic liver abscess)¹ since only limited data available.¹ ³² ⁶⁹

Adverse effects reported in pediatric patients generally similar in nature and frequency to those reported in adults.¹

Geriatric Use

Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults.¹

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

Hepatic Impairment

Use with caution;¹ pharmacokinetics not evaluated.¹

Studies using metronidazole (a chemically similar nitroimidazole) indicate reduced elimination and increased plasma concentrations in severe hepatic dysfunction.¹ ³¹

Renal Impairment

Dosage adjustment may be needed in patients undergoing hemodialysis.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects (metallic/bitter taste, nausea, anorexia, dyspepsia/cramps/epigastric discomfort, vomiting, constipation), nervous system effects (weakness/fatigue/malaise, dizziness, headache).¹

Interactions for Tinidazole

Metabolized principally by CYP3A4.¹

Does not inhibit CYP1A2, 2B6, 2C9, 2D6, 2E1, or 3A4 in vitro.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma tinidazole concentrations).¹

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma tinidazole concentrations).¹

Specific Drugs and Laboratory Tests

No formal drug interaction studies performed with tinidazole to date; interactions reported with metronidazole (a chemically similar nitroimidazole) may occur with tinidazole.¹

Drug or Test	Interaction	Comments
Alcohol	Alcoholic beverages or preparations containing alcohol or propylene glycol may cause abdominal cramps, nausea, vomiting, headaches, and flushing ¹	Avoid alcoholic beverages and preparations containing alcohol or propylene glycol during or for 3 days following completion of tinidazole therapy¹
Anticoagulants, oral (warfarin)	Possible increased PT and enhanced anticoagulant effects¹	Monitor PT and warfarin dosage carefully during concomitant use and for up to 8 days after the last tinidazole dose¹ ³²
Antifungal agents (ketoconazole)	Possible prolonged half-life, decreased clearance, and increased plasma concentrations of tinidazole¹
Cholestyramine	Studies using metronidazole indicate cholestyramine decreases oral bioavailability of the nitroimidazole by 21%¹	Give tinidazole and cholestyramine doses at separate times¹
Cimetidine	Possible prolonged half-life, decreased clearance, and increased plasma concentrations of tinidazole¹
Disulfiram	Experience with metronidazole and disulfiram indicates psychotic reactions can occur; such reactions not reported to date with tinidazole ¹ ³¹	Do not use concomitantly; do not initiate tinidazole until 2 weeks after disulfiram is discontinued¹
Fluorouracil	Experience with metronidazole and fluorouracil indicates decreased fluorouracil clearance, increased fluorouracil-associated adverse effects, no increased therapeutic benefit¹	If concomitant use of tinidazole and fluorouracil is unavoidable, monitor for fluorouracil toxicity¹
Immunosuppressive agents (cyclosporine, tacrolimus)	Experience with metronidazole indicates increased plasma concentrations of cyclosporine or tacrolimus¹	Monitor for cyclosporine or tacrolimus toxicity if tinidazole used concomitantly with one of these drugs¹
Lithium	Experience with metronidazole and lithium indicates increased lithium concentrations;¹ not reported to date with tinidazole¹	Measure serum lithium and creatinine concentrations after several days of concomitant lithium and tinidazole therapy to detect potential lithium intoxication¹
Phenobarbital	Possible increased elimination and decreased plasma concentrations of tinidazole¹
Phenytoin or fosphenytoin	Experience with oral metronidazole and IV phenytoin indicates prolonged phenytoin half-life and reduced phenytoin clearance;¹ not reported with oral phenytoin and oral metronidazole¹ Possible increased elimination and decreased plasma concentrations of tinidazole¹
Rifampin	Possible increased elimination and decreased plasma concentrations of tinidazole¹
Tests based on ultraviolet (UV) absorbance	Falsely decreased serum concentrations (including undetectable concentrations) of AST, ALT, LDH, triglycerides, or hexokinase glucose may be reported during tinidazole therapy if results are based on decreases in UV absorbance that occur during oxidation-reduction of NADH/NAD¹ UV absorbance peaks of NADH and tinidazole are similar¹	Use caution when interpreting test results based on UV absorbance during tinidazole therapy¹
Tetracyclines	Experience with metronidazole indicates oxytetracycline (no longer commercially available in the US) may inhibit therapeutic effects of the nitroimidazole¹

Tinidazole Pharmacokinetics

Absorption

Bioavailability

Estimated oral bioavailability >90%.⁶³

Rapidly absorbed following oral administration; peak plasma concentrations usually attained within about 2 hours.¹ ³² ⁶³ ⁶⁸

Pharmacokinetic parameters reported with extemporaneous oral suspension containing 66.7 mg/mL (prepared using crushed 500-mg tablets and cherry syrup) in healthy individuals after an overnight fast similar to those reported with tablets swallowed whole under fasted conditions.¹ ³²

Food

Administration with food delays time to peak plasma concentrations by approximately 2 hours and decreases peak plasma concentrations by 10%,¹ ³² but does not affect AUC or elimination half-life.¹ ³²

Distribution

Extent

Distributed into virtually all body tissues and body fluids.¹ ³² ⁶³

Crosses blood-brain barrier.¹ ³² ⁶³

Crosses placenta and is distributed into breast milk.¹

Plasma Protein Binding

12%.¹ ³² ⁶³

Elimination

Metabolism

Extensively metabolized prior to elimination.¹ ⁶³ ¹

Partially metabolized via oxidation, hydroxylation, and conjugation.¹ ⁶³ Metabolized principally by CYP3A4.¹

Present in plasma principally as unchanged drug with small amounts of the 2-hydroxymethyl metabolite.¹ ³² ⁶³

Elimination Route

Eliminated by the liver and kidneys.¹

Excreted in urine as unchanged drug (20–25%) and in feces (12%).¹ ³² ⁶³ ⁶⁸

Removed by hemodialysis.¹ ⁶⁰

Not known whether removed by CAPD.¹

Half-life

Approximately 12–14 hours.¹ ³² ⁵⁸ ⁶³ ⁶⁸

Special Populations

Hepatic impairment: Pharmacokinetics not evaluated.¹ Studies using metronidazole (a chemically similar nitroimidazole) indicate reduced elimination and increased plasma concentrations in severe hepatic impairment.¹ ³¹

Severe renal impairment: Pharmacokinetics not affected by severe impairment (Cl_cr <22 mL/min).¹

Hemodialysis patients: Clearance increased and elimination half-life decreased (from 12 hours to 4.9 hours).¹ ⁶⁰ (See Renal Impairment under Dosage and Administration.)

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C);¹ protect from light.¹

Extemporaneous Oral Suspension

Suspension containing 66.7 mg/mL: Stable for 7 days at room temperature.¹ (See Extemporaneous Oral Suspension under Dosage and Administration.)

Actions and SpectrumActions

Amebicidal, trichomonacidal, and bactericidal.¹ ³² ⁵⁸ ⁵⁹ ⁶³ ⁶⁴ ⁶⁵ ⁶⁸

Cell extracts of Trichomonas appear to reduce the nitroimidazole group of tinidazole and generate the free nitro radical, which may be responsible for the drug’s anti-infective activity.¹ ³² ⁵⁹ ⁶⁵ Mechanism of activity against Giardia and Entamoeba histolytica not known.¹

Protozoa: Active in vitro and in clinical infections against Trichomonas vaginalis, G. duodenalis (also known as G. lamblia or G. intestinalis), and E. histolytica.¹ ⁵⁸ ⁵⁹ ⁶⁵

Anaerobes: Active in vitro against many anaerobic bacteria including some Bacteroides⁵⁸ ⁶⁴ (e.g., B. fragilis,³² ⁵⁹ ⁶³ ⁶⁴ ⁶⁵ ⁶⁸ B. melaninogenicus⁶³ ), some Clostridium³² ⁵⁹ ⁶³ (e.g., C. difficile,³² C. perfringens⁶³ ⁶⁴ ), Prevotella,³² Fusobacterium,⁶³ ⁶⁴ ⁶⁸ Peptococcus,³² ⁵⁸ ⁵⁹ ⁶³ and Peptostreptococcus.³² ⁵⁸ ⁵⁹ ⁶³

Other organisms: Active against Helicobacter pylori ³² and Gardnerella vaginalis.³² ⁵⁹ ⁶⁵ Inactive against most Lactobacillus normally resident in vagina.¹ ³²

Potential for development of resistance in Giardia, E. histolytica, or bacteria associated with bacterial vaginosis not evaluated.¹

Although clinical importance unclear,⁶¹ some T. vaginalis with reduced susceptibility to metronidazole also have reduced susceptibility to tinidazole in vitro.¹ ⁶¹ ⁶² ⁶¹

Advice to Patients

Importance of taking with food to reduce the incidence of adverse GI effects (e.g., epigastric discomfort).¹

Advise patients to avoid alcoholic beverages and preparations containing alcohol or propylene glycol during and for at least 3 days after receiving tinidazole.¹

Advise patients to promptly discontinue tinidazole and contact clinician if abnormal neurologic signs occur.¹

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.¹

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

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

Tinidazole
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	250 mg	Tindamax (scored)	Mission
		500 mg	Tindamax (scored)	Mission

Comparative Pricing

Tindamax 500MG Tablets (MISSION): 20/$195.88 or 60/$556.36

Disclaimer

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Mission Pharmacal. Tindamax (tinidazole tablets) prescribing information. San Antonio, TX; 2007 Jul.

2. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website (). Accessed 2004 Aug.

3. Hager WD. Treatment of metronidazole-resistant Trichomonas vaginalis with tinidazole: case reports of three patients. Sex Transm Dis. 2004; 31:343-5. [PubMed 15167642]

4. Gulmezoglu AM, Garner P. Trichomoniasis treatment in women: a systematic review. Trop Med Int Health. 1998; 3:553-8. [IDIS 412104] [PubMed 9705189]

5. O-Prasertsawat P, Jetsawangsri T. Split-dose metronidazole or single-dose tinidazole for the treatment of vaginal trichomoniasis. Sex Transm Dis. 1992; 19:295-7. [IDIS 521309] [PubMed 1411848]

7. Lossick JG. Treatment of sexually transmitted vaginosis/vaginitis. Rev Infect Dis. 1990; 12(Suppl 6):S665-81. [IDIS 300932] [PubMed 2201078]

8. Heine P, McGregor JA. Trichomonas vaginalis: a reemerging pathogen. Clin Obstet Gynecol. 1993; 36:137-44. [PubMed 8435938]

9. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006; 55(RR-11):1-95.

10. Lossick JG. Treatment of Trichomonas vaginalis infections. Rev Infect Dis. 1982; 4(Suppl):S801-18.

11. Lossick JG, Kent HL. Trichomoniasis: trends in diagnosis and management. Am J Obstet Gynecol. 1991; 165:1217-22. [IDIS 290714] [PubMed 1951578]

13. Anjaeyulu R, Gupte SA, Desai DB. Single-dose treatment of trichomonal vaginitis: a comparison of tinidazole and metronidazole. J Int Med Res. 1977; 5:438-41. [PubMed 590601]

14. Bloch B, Smyth E. The treatment of Trichomonas vaginalis vaginitis: an open controlled prospective study comparing a single dose of metronidazole tablets, benzoyl metronidazole suspension and tinidazole tablets. S Afr Med J. 1985; 67:455-7. [IDIS 200360] [PubMed 3885425]

15. Lyng J, Christensen J. A double-blind study of the value of treatment with a single dose tinidazole of partners to females with trichomoniasis. Acta Obstet Gynecol Scand. 1981; 60:199-201. [PubMed 7018164]

16. Chaudhuri P, Drogendijk AC. A double-blind controlled clinical trial of carnidazole and tinidazole in the treatment of vaginal trichomoniasis. Eur J Obstet Gynecol Reprod Biol. 1980; 10:325-8. [PubMed 6995193]

17. Anon. Drugs for parasitic infections. From the Medical Letter web site (). Aug 2008.

18. American Academy of Pediatrics. 2006 Red Book: Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

19. Hill DR. Giardiasis: issues in diagnosis and management. Infect Dis Clin North Am. 1993; 7:503-25. [PubMed 8254157]

20. Ortega YR, Adam RD. Giardia: overview and update. Clin Infect Dis. 1997; 25:545-50. [IDIS 393721] [PubMed 9314441]

21. Nigam P, Kapoor KK, Kumar AJ et al. Clinical profile of giardiasis and comparison of its therapeutic response to metronidazole and tinidazole. J Assoc Physicians India. 1991; 39:613-5. [PubMed 1814877]

22. Gupta JP, Jain AK, Nanivadekar AS. Efficacy of tinidazole (Fasigyn) in giardiasis by parasitologic, biochemical, and gut transit studies. Indian J Gastroenterol. 1989; 8:103-4. [PubMed 2707840]

23. Cervetto JL, Ramonet M, Nahmod LH et al. Giardiasis. Functional, immunological and histological study of the small bowel: therapeutic trial with a single dose of tinidazole. Arg Gastroenterol. 1987; 24:102-12.

24. Speelman P. Single-dose tinidazole for the treatment of giardiasis. Antimicrob Agents Chemother. 1985; 27:227-9. [IDIS 196181] [PubMed 3985604]

25. Ravdin JI. Amebiasis. Clin Infect Dis. 1995; 20:1453-66. [IDIS 349015] [PubMed 7548493]

26. Aucott JN, Ravdin JI. Amebiasis and “nonpathogenic” intestinal protozoa. Infect Dis Clin North Am. 1993; 7:467-85. [PubMed 8254155]

27. Reed SL. Amebiasis: an update. Clin Infect Dis. 1992; 14:385-93. [IDIS 292053] [PubMed 1554822]

28. Lim JK. Clinical trial of tinidazole (Fasigyn) in acute and chronic intestinal Amoebiasis. Kisaengchunghak Chapchi. 1974; 12:135-140. [PubMed 12913475]

29. Salles JM, Bechara C, Tavares AM et al. Comparative study of the efficacy and tolerability of secnidazole suspension (single dose) and tinidazole suspension (two days dosage) in the treatment of amebiasis in children. Braz J Infect Dis. 1999; 3:80-88. [PubMed 11098194]

30. Boonyapisit S, Chinapak O, Plengvanit U. Amoebic liver abscess in Thailand, clinical analysis of 418 cases. J Med Assoc Thai. 1993;76:243-6.

31. G.D. Searle. Flagyl (metronidazole tablets) prescribing information. Chicago, IL; 2003 Aug.

32. Presutti Laboratories, Arlington Heights, IL: personal communication.

34. Centers for Disease Control and Prevention. Health information for international travel, 2005–2006. Atlanta, GA: US Department of Health and Human Services; 2005. Updates available from CDC website ().

35. Forna F, Gulmezoglu AM. Interventions for treating Trichomoniasis in women (Cochrane review). In: The Cochrane Library. Issue 2. Oxford, United Kingdom: update software 2004.

36. Gabriel G, Robertson E, Thin RN. Single dose treatment of trichomoniasis. J Int Med Res. 1982;10:129-30.

37. Rees PH, McGlashan HE, Mwega V. Single-dose treatment of vaginal trichomoniasis with tinidazole. East Afr Med J. 1974;51:782-5.

38. Mati JK, Wallace RJ. The treatment of trichomonal vaginitis using a single dose of tinidazole by mouth. East Afr Med J. 1974;51:883-8.

39. Sobel JD. Vaginitis. N Engl J Med.1997;337:1896-903.

40. Zaat JO, Mank T, Assendelft WJ. Drugs for treating giardiasis (Cochrane Database). In: The Cochrane Library. Issue 3. Oxford, United Kingdom: update software 2004.

41. Jokipii L, Jokipii AMM. Single-dose metronidazole and tinidazole as therapy for giardiasis: success rates, side effects, and drug absorption and elimination. J Infect Dis. 1979;140:984-88.

42. Danzig S, Hatchuel WLF. Single-dose treatment of giardiasis with tinidazole. S Afr Med J. 1974; 52:708.

43. Bakshi JS, Ghiara JM, Nanivadekar AS. How does tinidazole compare with metronidazole? Drugs. 1978;4315:33-42.

44. Gazder AJ & Banerjee M: Single-dose treatment of giardiasis in children: a comparison of tinidazole and metronidazole. Curr Med Res Opin. 1977; 5:164-68.

45. Centers for Disease Control and Prevention. CDC surveillance summaries: giardiasis surveillance United States, 1992–1997. MMWR CDC Surveill Summ. 2000;49:1-13.

46. Kyronseppa H, Pettersson T. Treatment of giardiasis: relative efficacy of metronidazole as compared with tinidazole. Scand J Inf Dis. .1981; 13:311-12.

47. Haque R, Huston CD, Hughes M, et al. Amebiasis. N Engl J Med. 2003;348:1565-73.

48. Mabadadeje AF, Oredugba. Single-dose tinidazole treatment of amebic dysentery. Curr Ther Res. 1977;21:685-8.

49. Swami B, Lavakusulu D, Devi CS. Tinidazole and metronidazole in the treatment of intestinal amoebiasis. Curr Med Res Opin. 1977;5:152-6.

50. Ahmed T, Ali F, Sarwar SG. Clinical evaluation of tinidazole in amoebiasis in children. Arch Dis Childhood. 1976;51:388-89.

51. Singh G, Kumar S. Short course of single daily dosage treatment with tinidazole and metronidazole in intestinal amoebiasis: a comparative study. Curr Med Res Opin. 1977;5:157-60.

52. Islam N, Hasan K. Tinidazole and metronidazole

Carmin

Carmin may be available in the countries listed below.

Ingredient matches for Carmin

Desogestrel

Desogestrel is reported as an ingredient of Carmin in the following countries:

Argentina

International Drug Name Search

Ibucaps

Ibucaps may be available in the countries listed below.

Ingredient matches for Ibucaps

Ibuprofen

Ibuprofen is reported as an ingredient of Ibucaps in the following countries:

Venezuela

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Wednesday, September 28, 2016

Trelstar

triptorelin pamoate

Dosage Form: injection, powder, lyophilized, for suspension
FULL PRESCRIBING INFORMATION

Indications and Usage for Trelstar

Trelstar is indicated for the palliative treatment of advanced prostate cancer [see Clinical Studies (14)].

Trelstar Dosage and Administration

Dosing Information

Trelstar must be administered under the supervision of a physician.

Trelstar is administered by a single intramuscular injection in either buttock. Dosing schedule depends on the product strength selected (Table 1). The lyophilized microgranules are to be reconstituted in sterile water. No other diluent should be used.

Table 1. Trelstar Recommended Dosing
Dosage	3.75 mg	11.25 mg	22.5 mg
Recommended dose	1 injection every 4 weeks	1 injection every 12 weeks	1 injection every 24 weeks

Due to different release characteristics, the dosage strengths are not additive and must be selected based upon the desired dosing schedule.

The suspension should be administered immediately after reconstitution.

As with other drugs administered by intramuscular injection, the injection site should be alternated periodically.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitution Instructions for Trelstar

Please read the instructions completely before you begin.

Wash your hands with soap and hot water and put on gloves immediately prior to preparing the injection.

Place the vial in a standing upright position on a clean, flat surface that is covered with a sterile pad or cloth.

Remove the Flip-Off® button from the top of the vial, revealing the rubber stopper.

Disinfect the rubber stopper with an alcohol wipe. Discard the alcohol wipe and allow the stopper to dry.

Using a syringe fitted with a sterile 21-gauge needle, withdraw 2 mL sterile water for injection, and inject into the vial.

Shake well to thoroughly disperse particles to obtain a uniform suspension. The suspension will appear milky.

Slowly withdraw the entire contents of the reconstituted suspension into the syringe.

The suspension should be administered immediately after reconstitution.

Inject the patient in either buttock with the contents of the syringe.

Reconstitution Instructions for Trelstar with MIXJECT SYSTEM

Please read the instructions completely before you begin.

MIXJECT Preparation

Wash your hands with soap and hot water and put on gloves immediately prior to preparing the injection. Place the sealed tray on a clean, flat surface that is covered with a sterile pad or cloth. Peel the cover away from the tray and remove the MIXJECT components and the Trelstar vial. Remove the Flip-Off button from the top of the vial, revealing the rubber stopper. Place the vial in a standing upright position on the prepared surface. Disinfect the rubber stopper with the alcohol wipe. Discard the alcohol wipe and allow the stopper to dry. Proceed to MIXJECT Activation.

MIXJECT Activation

Dosage Forms and Strengths

Injectable suspension: 3.75 mg, 11.25 mg, 22.5 mg.

Contraindications

Hypersensitivity

Trelstar is contraindicated in individuals with a known hypersensitivity to triptorelin or any other component of the product, or other GnRH agonists or GnRH [see Warnings and Precautions (5.1 )].

Pregnancy

Trelstar may cause fetal harm when administered to a pregnant woman. Expected hormonal changes that occur with Trelstar treatment increase the risk for pregnancy loss and fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Trelstar is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Warnings and Precautions

Hypersensitivity Reactions

Anaphylactic shock, hypersensitivity, and angioedema related to triptorelin administration have been reported. In the event of a hypersensitivity reaction, therapy with Trelstar should be discontinued immediately and the appropriate supportive and symptomatic care should be administered.

Transient Increase in Serum Testosterone

Initially, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a result, isolated cases of worsening of signs and symptoms of prostate cancer during the first weeks of treatment have been reported with GnRH agonists. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction [see Clinical Pharmacology (12.2)].

Metastatic Vertebral Lesions and Urinary Tract Obstruction

Cases of spinal cord compression, which may contribute to weakness or paralysis with or without fatal complications, have been reported with GnRH agonists. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy considered.

Patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy.

Hyperglycemia and Diabetes

Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.

Cardiovascular Diseases

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.

Laboratory Tests

Response to Trelstar should be monitored by measuring serum levels of testosterone periodically or as indicated.

Laboratory Test Interactions

Chronic or continuous administration of triptorelin in therapeutic doses results in suppression of pituitary-gonadal axis. Diagnostic tests of the pituitary-gonadal function conducted during treatment and after cessation of therapy may therefore be misleading.

Adverse Reactions

Clinical Trials Experience

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

The safety of the three Trelstar formulations was evaluated in clinical trials involving patients with advanced prostate cancer. Mean testosterone levels increased above baseline during the first week following the initial injection, declining thereafter to baseline levels or below by the end of the second week of treatment. The transient increase in testosterone levels may be associated with temporary worsening of disease signs and symptoms, including bone pain, neuropathy, hematuria, and urethral or bladder outlet obstruction. Isolated cases of spinal cord compression with weakness or paralysis of the lower extremities have occurred [see Warnings and Precautions (5.3)].

Adverse reactions reported for each of the three Trelstar formulations in the clinical trials, are presented in Table 2, Table 3, and Table 4. Often, causality is difficult to assess in patients with metastatic prostate cancer. The majority of adverse reactions related to triptorelin are a result of its pharmacological action, i.e., the induced variation in serum testosterone levels, either an increase in testosterone at the initiation of treatment, or a decrease in testosterone once castration is achieved. Local reactions at the injection site or allergic reactions may occur.

The following adverse reactions were reported to have a possible or probable relationship to therapy as ascribed by the treating physician in at least 1% of patients receiving Trelstar 3.75 mg.

Table 2. Trelstar 3.75 mg: Treatment-Related Adverse Reactions Reported by 1% or More of Patients During Treatment
* Adverse reactions for Trelstar 3.75 mg are coded using the WHO Adverse Reactions Terminology (WHOART)
Adverse Reactions*	Trelstar 3.75 mg N = 140
Adverse Reactions*	N	%
Application Site Disorders
Injection site pain	5	3.6
Body as a Whole
Hot flush	82	58.6
Pain	3	2.1
Leg pain	3	2.1
Fatigue	3	2.1
Cardiovascular Disorders
Hypertension	5	3.6
Central and Peripheral Nervous System Disorders
Headache	7	5.0
Dizziness	2	1.4
Gastrointestinal Disorders
Diarrhea	2	1.4
Vomiting	3	2.1
Musculoskeletal System Disorders
Skeletal pain	17	12.1
Psychiatric Disorders
Insomnia	3	2.1
Impotence	10	7.1
Emotional lability	2	1.4
Red Blood Cell Disorders
Anemia	2	1.4
Skin and Appendages Disorders
Pruritus	2	1.4
Urinary System Disorders
Urinary tract infection	2	1.4
Urinary retention	2	1.4

The following adverse reactions were reported to have a possible or probable relationship to therapy as ascribed by the treating physician in at least 1% of patients receiving Trelstar 11.25 mg.

Table 3. Trelstar 11.25 mg: Treatment-Related Adverse Reactions Reported by 1% or More of Patients During Treatment
* Adverse reactions for Trelstar 11.25 mg are coded using the WHO Adverse Reactions Terminology (WHOART)
Adverse Reactions*	Trelstar 11.25 mg N = 174
Adverse Reactions*	N	%
Application Site
Injection site pain	7	4.0
Body as a Whole
Hot flush	127	73.0
Leg pain	9	5.2
Pain	6	3.4
Back pain	5	2.9
Fatigue	4	2.3
Chest pain	3	1.7
Asthenia	2	1.1
Peripheral edema	2	1.1
Cardiovascular Disorders
Hypertension	7	4.0
Dependent edema	4	2.3
Central and Peripheral Nervous System Disorders
Headache	12	6.9
Dizziness	5	2.9
Leg cramps	3	1.7
Endocrine
Breast pain	4	2.3
Gynecomastia	3	1.7
Gastrointestinal Disorders
Nausea	5	2.9
Constipation	3	1.7
Dyspepsia	3	1.7
Diarrhea	2	1.1
Abdominal pain	2	1.1
Liver and Biliary System
Abnormal hepatic function	2	1.1
Metabolic and Nutritional Disorders
Edema in legs	11	6.3
Increased alkaline phosphatase	3	1.7
Musculoskeletal System Disorders
Skeletal pain	23	13.2
Arthralgia	4	2.3
Myalgia	2	1.1
Psychiatric Disorders
Decreased libido	4	2.3
Impotence	4	2.3
Insomnia	3	1.7
Anorexia	3	1.7
Respiratory System Disorders
Coughing	3	1.7
Dyspnea	2	1.1
Pharyngitis	2	1.1
Skin and Appendages
Rash	3	1.7
Urinary System Disorders
Dysuria	8	4.6
Urinary retention	2	1.1
Vision Disorders
Eye pain	2	1.1
Conjunctivitis	2	1.1

The following adverse reactions occurred in at least 5% of patients receiving Trelstar 22.5 mg. The table includes all reactions whether or not they were ascribed to Trelstar by the treating physician. The table also includes the incidence of these adverse reactions that were considered by the treating physician to have a reasonable causal relationship or for which the relationship could not be assessed.

Table 4. Trelstar 22.5 mg: Adverse Reactions Reported by 5% or More of Patients During Treatment
* Adverse reactions for Trelstar 22.5 mg are coded using the Medical Dictionary for Regulatory Activities (MedDRA)
Adverse Reactions*	Trelstar 22.5 mg N = 120
Adverse Reactions*	Treatment-Emergent		Treatment-Related
	N	%	N	%
General Disorders and Administration Site Conditions
Edema peripheral	6	5.0	0	0
Infections and Infestations
Influenza	19	15.8	0	0
Bronchitis	6	5.0	0	0
Endocrine
Diabetes Mellitus/Hyperglycemia	6	5.0	0	0
Musculoskeletal and Connective Tissue Disorders
Back pain	13	10.8	1	0.8
Arthralgia	9	7.5	1	0.8
Pain in extremity	9	7.5	1	0.8
Nervous System Disorders
Headache	9	7.5	2	1.7
Psychiatric Disorders
Insomnia	6	5.0	1	0.8
Renal and Urinary Disorders
Urinary tract infection	14	11.6	0	0
Urinary retention	6	5.0	0	0
Reproductive System and Breast Disorders
Erectile dysfunction	12	10.0	12	10.0
Testicular atrophy	9	7.5	9	7.5
Vascular Disorders
Hot flush	87	72.5	86	71.7
Hypertension	17	14.2	1	0.8

Changes in Laboratory Values During Treatment

The following abnormalities in laboratory values not present at baseline were observed in 10% or more of patients:

Trelstar 3.75 mg: There were no clinically meaningful changes in laboratory values detected during therapy.

Trelstar 11.25 mg: Decreased hemoglobin and RBC count and increased glucose, BUN, SGOT, SGPT, and alkaline phosphatase at the Day 253 visit.

Trelstar 22.5 mg: Decreased hemoglobin and increased glucose and hepatic transaminases were detected during the study. The majority of the changes were mild to moderate.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of gonadotropin releasing hormone agonists. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

During postmarketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

During postmarketing experience, thromboembolic events including, but not limited to, pulmonary emboli, cerebrovascular accident, myocardial infarction, deep venous thrombosis, transient ischemic attack, and thrombophlebitis have been reported.

Drug Interactions

No drug-drug interaction studies involving triptorelin have been conducted.

Human pharmacokinetic data with triptorelin suggest that C-terminal fragments produced by tissue degradation are either degraded completely within tissues or are rapidly degraded further in plasma, or cleared by the kidneys. Therefore, hepatic microsomal enzymes are unlikely to be involved in triptorelin metabolism. However, in the absence of relevant data and as a precaution, hyperprolactinemic drugs should not be used concomitantly with triptorelin since hyperprolactinemia reduces the number of pituitary GnRH receptors.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category X [see 'Contraindications' section].

Trelstar is contraindicated in women who are or may become pregnant while receiving the drug. Expected hormonal changes that occur with Trelstar treatment increase the risk for pregnancy loss. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Studies in pregnant rats administered triptorelin at doses of 2, 10, and 100 mcg/kg/day (approximately equivalent to 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area) during the period of organogenesis demonstrated maternal toxicity and embryo-fetal toxicities. Embryo-fetal toxicities consisted of pre-implantation loss, increased resorption, and reduced mean number of viable fetuses at the high dose. Teratogenic effects were not observed in viable fetuses in rats or mice. Doses administered to mice were 2, 20, and 200 mcg/kg/day (approximately equivalent to 0.1, 0.7, and 7 times the estimated human daily dose based on body surface area).

Nursing Mothers

Trelstar is not indicated for use in women [see Indications and Usage (1)]. It is not known if triptorelin is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Trelstar, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Prostate cancer occurs primarily in an older population. Clinical studies with Trelstar have been conducted primarily in patients ≥ 65 years [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

Renal Impairment

Subjects with renal impairment had higher exposure than young healthy males [see Clinical Pharmacology (12.3)].

Hepatic Impairment

Subjects with hepatic impairment had higher exposure than young healthy males [see Clinical Pharmacology (12.3)].

Overdosage

There is no experience of overdosage in clinical trials. In single dose toxicity studies in mice and rats, the subcutaneous LD50 of triptorelin was 400 mg/kg in mice and 250 mg/kg in rats, approximately 500 and 600 times, respectively, the estimated monthly human dose based on body surface area. If overdosage occurs, therapy should be discontinued immediately and the appropriate supportive and symptomatic treatment administered.

Trelstar Description

Trelstar is a white to slightly yellow lyophilized cake. When reconstituted, Trelstar has a milky appearance. It contains a pamoate salt of triptorelin, a synthetic decapeptide agonist analog of gonadotropin releasing hormone (GnRH). The chemical name of triptorelin pamoate is 5 - oxo - L - prolyl - L - histidyl - L - tryptophyl - L - seryl - L - tyrosyl - D - tryptophyl - L - leucyl - L - arginyl - L - prolylglycine amide (pamoate salt). The empirical formula is C64H82N18O13 · C23H16O6 and the molecular weight is 1699.9. The structural formula is:

The Trelstar products are sterile, lyophilized biodegradable microgranule formulations supplied as single dose vials. Refer to Table 5 for the composition of each Trelstar product.

Table 5. Trelstar Composition
Ingredients	Trelstar 3.75 mg	Trelstar 11.25 mg	Trelstar 22.5 mg
triptorelin pamoate (base units)	3.75 mg	11.25 mg	22.5 mg
poly-d,l-lactide-co-glycolide	136 mg	118 mg	182 mg
mannitol, USP	69 mg	76 mg	68 mg
carboxymethylcellulose sodium, USP	24 mg	27 mg	24 mg
polysorbate 80, NF	1.6 mg	1.8 mg	1.6 mg

When 2 mL sterile water is added to the vial containing Trelstar and mixed, a suspension is formed which is intended as an intramuscular injection. Trelstar is available in two packaging configurations: (a) Trelstar vial alone or (b) Trelstar vial plus a MIXJECT vial adapter, and a separate pre-filled syringe that contains sterile water for injection, USP, 2 mL, pH 6 to 8.5.

Trelstar - Clinical Pharmacology

Mechanism of Action

Triptorelin is a synthetic decapeptide agonist analog of gonadotropin releasing hormone (GnRH). Comparative in vitro studies showed that triptorelin was 100-fold more active than native GnRH in stimulating luteinizing hormone release from monolayers of dispersed rat pituitary cells in culture and 20-fold more active than native GnRH in displacing 125I-GnRH from pituitary receptor sites. In animal studies, triptorelin pamoate was found to have 13‑fold higher luteinizing hormone-releasing activity and 21-fold higher follicle-stimulating hormone-releasing activity compared to the native GnRH.

Pharmacodynamics

Following the first administration, there is a transient surge in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol [see Adverse Reactions (6)]. After chronic and continuous administration, usually 2 to 4 weeks after initiation of therapy, a sustained decrease in LH and FSH secretion and marked reduction of testicular steroidogenesis are observed. A reduction of serum testosterone concentration to a level typically seen in surgically castrated men is obtained. Consequently, the result is that tissues and functions that depend on these hormones for maintenance become quiescent. These effects are usually reversible after cessation of therapy.

Following a single intramuscular injection of Trelstar:

Trelstar 3.75 mg: serum testosterone levels first increased, peaking on Day 4, and declined thereafter to low levels by Week 4 in healthy male volunteers.

Trelstar 11.25 mg: serum testosterone levels first increased, peaking on Days 2 – 3, and declined thereafter to low levels by Weeks 3 – 4 in men with advanced prostate cancer.

Trelstar 22.5 mg: serum testosterone levels first increased, peaking on Day 3, and declined thereafter to low levels by Weeks 3 – 4 in men with advanced prostate cancer.

Pharmacokinetics

Results of pharmacokinetic investigations conducted in healthy men indicate that after intravenous bolus administration, triptorelin is distributed and eliminated according to a 3-compartment model and corresponding half-lives are approximately 6 minutes, 45 minutes, and 3 hours.

Absorption

Following a single intramuscular injection of Trelstar to patients with prostate cancer, mean peak serum concentrations of 28.4 ng/mL, 38.5 ng/mL, and 44.1 ng/mL occurred in 1 to 3 hours after the 3.75 mg, 11.25 mg, and 22.5 mg formulations, respectively.

Triptorelin did not accumulate over 9 months (3.75 mg and 11.25 mg) or 12 months (22.5 mg) of treatment.

Distribution

The volume of distribution following a single intravenous bolus dose of 0.5 mg of triptorelin peptide was 30 – 33 L in healthy male volunteers. There is no evidence that triptorelin, at clinically relevant concentrations, binds to plasma proteins.

Metabolism

The metabolism of triptorelin in humans is unknown, but is unlikely to involve hepatic microsomal enzymes (cytochrome P-450). The effect of triptorelin on the activity of other drug metabolizing enzymes is also unknown. Thus far, no metabolites of triptorelin have been identified. Pharmacokinetic data suggest that C-terminal fragments produced by tissue degradation are either completely degraded in the tissues, or rapidly degraded in plasma, or cleared by the kidneys.

Excretion

Triptorelin is eliminated by both the liver and the kidneys. Following intravenous administration of 0.5 mg triptorelin peptide to six healthy male volunteers with a creatinine clearance of 149.9 mL/min, 41.7% of the dose was excreted in urine as intact peptide with a total triptorelin clearance of 211.9 mL/min. This percentage increased to 62.3% in patients with liver disease who have a lower creatinine clearance (89.9 mL/min). It has also been observed that the nonrenal clearance of triptorelin (patient anuric, CIcreat = 0) was 76.2 mL/min, thus indicating that the nonrenal elimination of triptorelin is mainly dependent on the liver.

Special Populations

Age and Race

The effects of age and race on triptorelin pharmacokinetics have not been systematically studied. However, pharmacokinetic data obtained in young healthy male volunteers aged 20 to 22 years with an elevated creatinine clearance (approximately 150 mL/min) indicate that triptorelin was eliminated twice as fast in this young population as compared with patients with moderate renal insufficiency. This is related to the fact that triptorelin clearance is partly correlated to total creatinine clearance, which is well known to decrease with age [see Use in Specific Populations (8.6) and (8.7)].

Pediatric

Trelstar has not been evaluated in patients less than 18 years of age [see Use in Specific Populations (8.4)].

Hepatic and Renal Impairment

After an intravenous bolus injection of 0.5 mg triptorelin, the two distribution half-lives were unaffected by renal and hepatic impairment. However, renal insufficiency led to a decrease in total triptorelin clearance proportional to the decrease in creatinine clearance as well as increases in volume of distribution and consequently, an increase in elimination half-life (see Table 6). In subjects with hepatic insufficiency, a decrease in triptorelin clearance was more pronounced than that observed with renal insufficiency. Due to minimal increases in the volume of distribution, the elimination half-life in subjects with hepatic insufficiency was similar to subjects with renal insufficiency. Subjects with renal or hepatic impairment had 2‑ to 4-fold higher exposure (AUC values) than young healthy males [see Use in Specific Populations (8.6) and (8.7)].

Table 6. Pharmacokinetic Parameters (Mean ± SD) in Healthy Volunteers and Special Populations Following an IV Bolus Injection of 0.5 mg Triptorelin
Group	Cmax (ng/mL)	AUCinf (h·ng/mL)	Clp (mL/min)	Clrenal (mL/min)	t1/2 (h)	Clcreat (mL/min)
6 healthy male volunteers	48.2 ±11.8	36.1 ±5.8	211.9 ±31.6	90.6 ±35.3	2.81 ±1.21	149.9 ±7.3
6 males with moderate renal impairment	45.6 ±20.5	69.9 ±24.6	120.0 ±45.0	23.3 ±17.6	6.56 ±1.25	39.7 ±22.5
6 males with severe renal impairment	46.5 ±14.0	88.0 ±18.4	88.6 ±19.7	4.3 ±2.9	7.65 ±1.25	8.9 ±6.0
6 males with liver disease	54.1 ±5.3	131.9 ±18.1	57.8 ±8.0	35.9 ±5.0	7.58 ±1.17	89