Stromectol

ivermectin

Dosage Form: tablet
Stromectol®

(IVERMECTIN)

TABLETS

Stromectol Description

Stromectol1 (Ivermectin) is a semisynthetic, anthelmintic agent for oral administration. Ivermectin is derived from the avermectins, a class of highly active broad-spectrum, anti-parasitic agents isolated from the fermentation products of Streptomyces avermitilis. Ivermectin is a mixture containing at least 90% 5-O-demethyl-22,23-dihydroavermectin A1a and less than 10% 5-O-demethyl-25-de(1-methylpropyl)-22,23-dihydro-25-(1-methylethyl)avermectin A1a, generally referred to as 22,23-dihydroavermectin B1a and B1b, or H2B1a and H2B1b, respectively. The respective empirical formulas are C48H74O14 and C47H72O14, with molecular weights of 875.10 and 861.07, respectively. The structural formulas are:

Ivermectin is a white to yellowish-white, nonhygroscopic, crystalline powder with a melting point of about 155°C. It is insoluble in water but is freely soluble in methanol and soluble in 95% ethanol.

Stromectol is available in 3-mg tablets containing the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, magnesium stearate, butylated hydroxyanisole, and citric acid powder (anhydrous).

1

Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Copyright © 1996, 2007 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

All rights reserved

Stromectol - Clinical Pharmacology

Pharmacokinetics

Following oral administration of ivermectin, plasma concentrations are approximately proportional to the dose. In two studies, after single 12-mg doses of Stromectol in fasting healthy volunteers (representing a mean dose of 165 mcg/kg), the mean peak plasma concentrations of the major component (H2B1a) were 46.6 (±21.9) (range: 16.4-101.1) and 30.6 (±15.6) (range: 13.9-68.4) ng/mL, respectively, at approximately 4 hours after dosing. Ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in the urine. The plasma half-life of ivermectin in man is approximately 18 hours following oral administration.

The safety and pharmacokinetic properties of ivermectin were further assessed in a multiple-dose clinical pharmacokinetic study involving healthy volunteers. Subjects received oral doses of 30 to 120 mg (333 to 2000 mcg/kg) ivermectin in a fasted state or 30 mg (333 to 600 mcg/kg) ivermectin following a standard high-fat (48.6 g of fat) meal. Administration of 30 mg ivermectin following a high-fat meal resulted in an approximate 2.5-fold increase in bioavailability relative to administration of 30 mg ivermectin in the fasted state.

In vitro studies using human liver microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4. Depending on the in vitro method used, CYP2D6 and CYP2E1 were also shown to be involved in the metabolism of ivermectin but to a significantly lower extent compared to CYP3A4. The findings of in vitro studies using human liver microsomes suggest that clinically relevant concentrations of ivermectin do not significantly inhibit the metabolizing activities of CYP3A4, CYP2D6, CYP2C9, CYP1A2, and CYP2E1.

Microbiology

Ivermectin is a member of the avermectin class of broad-spectrum antiparasitic agents which have a unique mode of action. Compounds of the class bind selectively and with high affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells. This leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. Compounds of this class may also interact with other ligand-gated chloride channels, such as those gated by the neurotransmitter gamma-aminobutyric acid (GABA).

The selective activity of compounds of this class is attributable to the facts that some mammals do not have glutamate-gated chloride channels and that the avermectins have a low affinity for mammalian ligand-gated chloride channels. In addition, ivermectin does not readily cross the blood-brain barrier in humans.

Ivermectin is active against various life-cycle stages of many but not all nematodes. It is active against the tissue microfilariae of Onchocerca volvulus but not against the adult form. Its activity against Strongyloides stercoralis is limited to the intestinal stages.

Clinical Studies

Strongyloidiasis

Two controlled clinical studies using albendazole as the comparative agent were carried out in international sites where albendazole is approved for the treatment of strongyloidiasis of the gastrointestinal tract, and three controlled studies were carried out in the U.S. and internationally using thiabendazole as the comparative agent. Efficacy, as measured by cure rate, was defined as the absence of larvae in at least two follow-up stool examinations 3 to 4 weeks post-therapy. Based on this criterion, efficacy was significantly greater for Stromectol (a single dose of 170 to 200 mcg/kg) than for albendazole (200 mg b.i.d. for 3 days). Stromectol administered as a single dose of 200 mcg/kg for 1 day was as efficacious as thiabendazole administered at 25 mg/kg b.i.d. for 3 days.

Summary of Cure Rates for Ivermectin Versus Comparative Agents in the Treatment of Strongyloidiasis

	Cure Rate*(%)
	Ivermectin†	Comparative Agent
* Number and % of evaluable patients † 170-200 mcg/kg ‡ 200 mg b.i.d. for 3 days § 25 mg/kg b.i.d. for 3 days
Albendazole‡ Comparative    International Study    WHO Study	24/26 (92) 126/152 (83)	12/22 (55) 67/149 (45)
Thiabendazole§ Comparative    International Study    US Studies	9/14 (64) 14/14 (100)	13/15 (87) 16/17 (94)

In one study conducted in France, a non-endemic area where there was no possibility of reinfection, several patients were observed to have recrudescence of Strongyloides larvae in their stool as long as 106 days following ivermectin therapy. Therefore, at least three stool examinations should be conducted over the three months following treatment to ensure eradication. If recrudescence of larvae is observed, retreatment with ivermectin is indicated. Concentration techniques (such as using a Baermann apparatus) should be employed when performing these stool examinations, as the number of Strongyloides larvae per gram of feces may be very low.

Onchocerciasis

The evaluation of Stromectol in the treatment of onchocerciasis is based on the results of clinical studies involving 1278 patients. In a double-blind, placebo-controlled study involving adult patients with moderate to severe onchocercal infection, patients who received a single dose of 150 mcg/kg Stromectol experienced an 83.2% and 99.5% decrease in skin microfilariae count (geometric mean) 3 days and 3 months after the dose, respectively. A marked reduction of >90% was maintained for up to 12 months after the single dose. As with other microfilaricidal drugs, there was an increase in the microfilariae count in the anterior chamber of the eye at day 3 after treatment in some patients. However, at 3 and 6 months after the dose, a significantly greater percentage of patients treated with Stromectol had decreases in microfilariae count in the anterior chamber than patients treated with placebo.

In a separate open study involving pediatric patients ages 6 to 13 (n=103; weight range: 17-41 kg), similar decreases in skin microfilariae counts were observed for up to 12 months after dosing.

Indications and Usage for Stromectol

Stromectol is indicated for the treatment of the following infections:

Strongyloidiasis of the intestinal tract. Stromectol is indicated for the treatment of intestinal (i.e., nondisseminated) strongyloidiasis due to the nematode parasite Strongyloides stercoralis.

This indication is based on clinical studies of both comparative and open-label designs, in which 64-100% of infected patients were cured following a single 200-mcg/kg dose of ivermectin. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

Onchocerciasis. Stromectol is indicated for the treatment of onchocerciasis due to the nematode parasite Onchocerca volvulus.

This indication is based on randomized, double-blind, placebo-controlled and comparative studies conducted in 1427 patients in onchocerciasis-endemic areas of West Africa. The comparative studies used diethylcarbamazine citrate (DEC-C).

NOTE: Stromectol has no activity against adult Onchocerca volvulus parasites. The adult parasites reside in subcutaneous nodules which are infrequently palpable. Surgical excision of these nodules (nodulectomy) may be considered in the management of patients with onchocerciasis, since this procedure will eliminate the microfilariae-producing adult parasites.

Contraindications

Stromectol is contraindicated in patients who are hypersensitive to any component of this product.

Warnings

Historical data have shown that microfilaricidal drugs, such as diethylcarbamazine citrate (DEC-C), might cause cutaneous and/or systemic reactions of varying severity (the Mazzotti reaction) and ophthalmological reactions in patients with onchocerciasis. These reactions are probably due to allergic and inflammatory responses to the death of microfilariae. Patients treated with Stromectol for onchocerciasis may experience these reactions in addition to clinical adverse reactions possibly, probably, or definitely related to the drug itself. (See ADVERSE REACTIONS, Onchocerciasis.)

The treatment of severe Mazzotti reactions has not been subjected to controlled clinical trials. Oral hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been used to treat postural hypotension. Antihistamines and/or aspirin have been used for most mild to moderate cases.

Precautions

General

After treatment with microfilaricidal drugs, patients with hyperreactive onchodermatitis (sowda) may be more likely than others to experience severe adverse reactions, especially edema and aggravation of onchodermatitis.

Rarely, patients with onchocerciasis who are also heavily infected with Loa loa may develop a serious or even fatal encephalopathy either spontaneously or following treatment with an effective microfilaricide. In these patients, the following adverse experiences have also been reported: pain (including neck and back pain), red eye, conjunctival hemorrhage, dyspnea, urinary and/or fecal incontinence, difficulty in standing/walking, mental status changes, confusion, lethargy, stupor, seizures, or coma. This syndrome has been seen very rarely following the use of ivermectin. In individuals who warrant treatment with ivermectin for any reason and have had significant exposure to Loa loa-endemic areas of West or Central Africa, pretreatment assessment for loiasis and careful post-treatment follow-up should be implemented.

Information for Patients

Stromectol should be taken on an empty stomach with water. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.)

Strongyloidiasis: The patient should be reminded of the need for repeated stool examinations to document clearance of infection with Strongyloides stercoralis.

Onchocerciasis: The patient should be reminded that treatment with Stromectol does not kill the adult Onchocerca parasites, and therefore repeated follow-up and retreatment is usually required.

Drug Interactions

Post-marketing reports of increased INR (International Normalized Ratio) have been rarely reported when ivermectin was co-administered with warfarin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of ivermectin.

Ivermectin was not genotoxic in vitro in the Ames microbial mutagenicity assay of Salmonella typhimurium strains TA1535, TA1537, TA98, and TA100 with and without rat liver enzyme activation, the Mouse Lymphoma Cell Line L5178Y (cytotoxicity and mutagenicity) assays, or the unscheduled DNA synthesis assay in human fibroblasts.

Ivermectin had no adverse effects on the fertility in rats in studies at repeated doses of up to 3 times the maximum recommended human dose of 200 mcg/kg (on a mg/m2/day basis).

Pregnancy

Teratogenic Effects

Pregnancy Category C

Ivermectin has been shown to be teratogenic in mice, rats, and rabbits when given in repeated doses of 0.2, 8.1, and 4.5 times the maximum recommended human dose, respectively (on a mg/m2/day basis). Teratogenicity was characterized in the three species tested by cleft palate; clubbed forepaws were additionally observed in rabbits. These developmental effects were found only at or near doses that were maternotoxic to the pregnant female. Therefore, ivermectin does not appear to be selectively fetotoxic to the developing fetus. There are, however, no adequate and well-controlled studies in pregnant women. Ivermectin should not be used during pregnancy since safety in pregnancy has not been established.

Nursing Mothers

Stromectol is excreted in human milk in low concentrations. Treatment of mothers who intend to breast-feed should only be undertaken when the risk of delayed treatment to the mother outweighs the possible risk to the newborn.

Pediatric Use

Safety and effectiveness in pediatric patients weighing less than 15 kg have not been established.

Geriatric Use

Clinical studies of Stromectol 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, treatment of 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.

Strongyloidiasis in Immunocompromised Hosts

In immunocompromised (including HIV-infected) patients being treated for intestinal strongyloidiasis, repeated courses of therapy may be required. Adequate and well-controlled clinical studies have not been conducted in such patients to determine the optimal dosing regimen. Several treatments, i.e., at 2-week intervals, may be required, and cure may not be achievable. Control of extra-intestinal strongyloidiasis in these patients is difficult, and suppressive therapy, i.e., once per month, may be helpful.

Adverse Reactions

Strongyloidiasis

In four clinical studies involving a total of 109 patients given either one or two doses of 170 to 200 mcg/kg of Stromectol, the following adverse reactions were reported as possibly, probably, or definitely related to Stromectol:

Body as a Whole: asthenia/fatigue (0.9%), abdominal pain (0.9%)

Gastrointestinal: anorexia (0.9%), constipation (0.9%), diarrhea (1.8%), nausea (1.8%), vomiting (0.9%)

Nervous System/Psychiatric: dizziness (2.8%), somnolence (0.9%), vertigo (0.9%), tremor (0.9%)

Skin: pruritus (2.8%), rash (0.9%), and urticaria (0.9%).

In comparative trials, patients treated with Stromectol experienced more abdominal distention and chest discomfort than patients treated with albendazole. However, Stromectol was better tolerated than thiabendazole in comparative studies involving 37 patients treated with thiabendazole.

The Mazzotti-type and ophthalmologic reactions associated with the treatment of onchocerciasis or the disease itself would not be expected to occur in strongyloidiasis patients treated with Stromectol. (See ADVERSE REACTIONS, Onchocerciasis.)

Laboratory Test Findings

In clinical trials involving 109 patients given either one or two doses of 170 to 200 mcg/kg Stromectol, the following laboratory abnormalities were seen regardless of drug relationship: elevation in ALT and/or AST (2%), decrease in leukocyte count (3%). Leukopenia and anemia were seen in one patient.

Onchocerciasis

In clinical trials involving 963 adult patients treated with 100 to 200 mcg/kg Stromectol, worsening of the following Mazzotti reactions during the first 4 days post-treatment were reported: arthralgia/synovitis (9.3%), axillary lymph node enlargement and tenderness (11.0% and 4.4%, respectively), cervical lymph node enlargement and tenderness (5.3% and 1.2%, respectively), inguinal lymph node enlargement and tenderness (12.6% and 13.9%, respectively), other lymph node enlargement and tenderness (3.0% and 1.9%, respectively), pruritus (27.5%), skin involvement including edema, papular and pustular or frank urticarial rash (22.7%), and fever (22.6%). (See WARNINGS.)

In clinical trials, ophthalmological conditions were examined in 963 adult patients before treatment, at day 3, and months 3 and 6 after treatment with 100 to 200 mcg/kg Stromectol. Changes observed were primarily deterioration from baseline 3 days post-treatment. Most changes either returned to baseline condition or improved over baseline severity at the month 3 and 6 visits. The percentages of patients with worsening of the following conditions at day 3, month 3 and 6, respectively, were: limbitis: 5.5%, 4.8%, and 3.5% and punctate opacity: 1.8%, 1.8%, and 1.4%. The corresponding percentages for patients treated with placebo were: limbitis: 6.2%, 9.9%, and 9.4% and punctate opacity: 2.0%, 6.4%, and 7.2%. (See WARNINGS.)

In clinical trials involving 963 adult patients who received 100 to 200 mcg/kg Stromectol, the following clinical adverse reactions were reported as possibly, probably, or definitely related to the drug in ≥1% of the patients: facial edema (1.2%), peripheral edema (3.2%), orthostatic hypotension (1.1%), and tachycardia (3.5%). Drug-related headache and myalgia occurred in <1% of patients (0.2% and 0.4%, respectively). However, these were the most common adverse experiences reported overall during these trials regardless of causality (22.3% and 19.7%, respectively).

A similar safety profile was observed in an open study in pediatric patients ages 6 to 13.

The following ophthalmological side effects do occur due to the disease itself but have also been reported after treatment with Stromectol: abnormal sensation in the eyes, eyelid edema, anterior uveitis, conjunctivitis, limbitis, keratitis, and chorioretinitis or choroiditis. These have rarely been severe or associated with loss of vision and have generally resolved without corticosteroid treatment.

Laboratory Test Findings

In controlled clinical trials, the following laboratory adverse experiences were reported as possibly, probably, or definitely related to the drug in ≥1% of the patients: eosinophilia (3%) and hemoglobin increase (1%).

Post-Marketing Experience

The following adverse reactions have been reported since the drug was registered overseas:

Onchocerciasis

Conjunctival hemorrhage

All Indications

Hypotension (mainly orthostatic hypotension), worsening of bronchial asthma, toxic epidermal necrolysis, Stevens-Johnson syndrome, seizures, hepatitis, elevation of liver enzymes, and elevation of bilirubin.

Overdosage

Significant lethality was observed in mice and rats after single oral doses of 25 to 50 mg/kg and 40 to 50 mg/kg, respectively. No significant lethality was observed in dogs after single oral doses of up to 10 mg/kg. At these doses, the treatment-related signs that were observed in these animals include ataxia, bradypnea, tremors, ptosis, decreased activity, emesis, and mydriasis.

In accidental intoxication with, or significant exposure to, unknown quantities of veterinary formulations of ivermectin in humans, either by ingestion, inhalation, injection, or exposure to body surfaces, the following adverse effects have been reported most frequently: rash, edema, headache, dizziness, asthenia, nausea, vomiting, and diarrhea. Other adverse effects that have been reported include: seizure, ataxia, dyspnea, abdominal pain, paresthesia, urticaria, and contact dermatitis.

In case of accidental poisoning, supportive therapy, if indicated, should include parenteral fluids and electrolytes, respiratory support (oxygen and mechanical ventilation if necessary) and pressor agents if clinically significant hypotension is present. Induction of emesis and/or gastric lavage as soon as possible, followed by purgatives and other routine anti-poison measures, may be indicated if needed to prevent absorption of ingested material.

Stromectol Dosage and Administration

Strongyloidiasis

The recommended dosage of Stromectol for the treatment of strongyloidiasis is a single oral dose designed to provide approximately 200 mcg of ivermectin per kg of body weight. See Table 1 for dosage guidelines. Patients should take tablets on an empty stomach with water. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) In general, additional doses are not necessary. However, follow-up stool examinations should be performed to verify eradication of infection. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

Table 1: Dosage Guidelines for Stromectol for Strongyloidiasis

Body Weight (kg)	Single Oral Dose
	Number of 3-mg Tablets
15-24	1 tablet
25-35	2 tablets
36-50	3 tablets
51-65	4 tablets
66-79	5 tablets
≥80	200 mcg/kg

Onchocerciasis

The recommended dosage of Stromectol for the treatment of onchocerciasis is a single oral dose designed to provide approximately 150 mcg of ivermectin per kg of body weight. See Table 2 for dosage guidelines. Patients should take tablets on an empty stomach with water. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) In mass distribution campaigns in international treatment programs, the most commonly used dose interval is 12 months. For the treatment of individual patients, retreatment may be considered at intervals as short as 3 months.

Table 2: Dosage Guidelines for Stromectol for Onchocerciasis

Body Weight (kg)	Single Oral Dose
	Number of 3-mg Tablets
15-25	1 tablet
26-44	2 tablets
45-64	3 tablets
65-84	4 tablets
≥85	150 mcg/kg

How is Stromectol Supplied

No. 8495 — Tablets Stromectol 3 mg are white, round, flat, bevel-edged tablets coded MSD on one side and 32 on the other side. They are supplied as follows:

NDC 0006-0032-20 unit dose packages of 20.

Storage

Store at temperatures below 30°C (86°F).

Dist. by: Merck Sharp & Dohme Corp., a subsidiary of

MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Manufactured by:

Merck Sharp & Dohme BV

Waarderweg 39

2031 BN Haarlem

Netherlands

Issued May 2010

Printed in the Netherlands

9032319

87447/080610

8495

This is a representative sample of the packaging. Please see How Supplied section for a complete list of available packaging.


PRINCIPAL DISPLAY PANEL - Carton 3 mg

Stromectol® 3 mg

(Ivermectin Tablets)

Manuf. by:

Merck Sharp & Dohme BV

Waarderweg 39

2031 BN Haarlem, Netherlands

Formulated in Netherlands

Dist. by: Merck Sharp & Dohme Corp., a subsidiary of

MERCK & CO., INC.

Whitehouse Station, NJ 08889, USA

Each tablet contains 3 mg of ivermectin.

USUAL DOSAGE: See accompanying circular.

Store at temperatures below 30°C (86°F).

Rx only

20 Tablets

(2 Foil Strips of 10 tablets each)

NDC 0006-0032-20

This is a bulk package and not intended for dispensing. The aluminum foil strip is not child resistant. Remove tablets from aluminum foil strip and dispense tablets in appropriate container.

20 | No. 8495 (US)

9994502

Stromectol  ivermectin  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0006-0032 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength IVERMECTIN (IVERMECTIN) IVERMECTIN 3 mg

Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE   STARCH, CORN   MAGNESIUM STEARATE   BUTYLATED HYDROXYANISOLE   ANHYDROUS CITRIC ACID

Product Characteristics Color WHITE (white) Score no score Shape ROUND (round) Size 6mm Flavor Imprint Code MSD;32 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0006-0032-20 2 BLISTER PACK In 1 CARTON contains a BLISTER PACK 1 10 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0006-0032-20)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA050742	11/22/1996

Labeler - Merck Sharp & Dohme Corp. (001317064)

Establishment
Name	Address	ID/FEI	Operations
Merck Sharp & Dohme BV		402003297	MANUFACTURE

Revised: 05/2010Merck Sharp & Dohme Corp.

More Stromectol resources

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

• Stromectol Concise Consumer Information (Cerner Multum)


• Stromectol Monograph (AHFS DI)


• Stromectol Advanced Consumer (Micromedex) - Includes Dosage Information


• Stromectol MedFacts Consumer Leaflet (Wolters Kluwer)

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Kinlytic

Generic Name: urokinase (Intravenous route)

ure-oh-KYE-nase

Commonly used brand name(s)

In the U.S.

• Abbokinase


• Kinlytic

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Thrombolytic

Pharmacologic Class: Tissue Plasminogen Activator

Uses For Kinlytic

Urokinase injection is used to dissolve blood clots that have formed in the lungs (pulmonary embolism).

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

This medicine is not available in the United States as of October 2010.

Before Using Kinlytic

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of urokinase injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

No information is available on the relationship of age to the effects of urokinase injection in geriatric patients.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol


• Alteplase, Recombinant


• Anistreplase


• Ardeparin


• Argatroban


• Bivalirudin


• Certoparin


• Dabigatran Etexilate


• Dalteparin


• Danaparoid


• Desirudin


• Drotrecogin Alfa


• Enoxaparin


• Fondaparinux


• Heparin


• Lepirudin


• Nadroparin


• Parnaparin


• Phenindione


• Phenprocoumon


• Protein C, Human


• Reteplase, Recombinant


• Reviparin


• Rivaroxaban


• Streptokinase


• Tenecteplase


• Tinzaparin


• Urokinase


• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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

• Bleeding problems or a history of bleeding in any part of the body or


• Blood vessel problems (e.g., aneurysm) or


• Brain disease or tumor or


• Hypertension (high blood pressure), uncontrolled or


• Stroke, recent (within two months) or


• Surgery or injury to the brain or spine, recent (within two months) or


• Trauma including CPR (cardiopulmonary resuscitation), recent—Should not be used in patients with these conditions.

• Blood clotting disorders or


• Diabetic eye problems (e.g., hemorrhagic retinopathy) or


• Heart disease or infections (e.g., endocarditis, mitral stenosis) or


• Injections into a blood vessel or


• Kidney disease, severe or


• Liver disease, severe or


• Placement of any tube into the body or


• Surgery or injury of any kind, major and recent—The chance of serious bleeding may be increased.

• High cholesterol, history of—The chance of having a serious side effect may be increased.

Proper Use of urokinase

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

A doctor or other trained health professional will give you this medicine. This medicine is given through a needle placed into one of your veins.

Precautions While Using Kinlytic

Urokinase can cause bleeding that usually is not serious. However, serious bleeding may occur in some people. To help prevent serious bleeding, carefully follow any instructions given by your doctor. Move around as little as possible, and do not get out of bed on your own, unless your doctor tells you it is all right to do so.

Watch for any bleeding or oozing on your skin, such as around the place of injection or where blood was drawn from your arm. Also, check for blood in your urine or bowel movements. If you have any bleeding or injuries, tell your doctor or nurse right away.

Kinlytic Side Effects

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

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

More common

• Bleeding gums


• coughing up blood


• difficulty with breathing or swallowing


• dizziness


• headache


• increased menstrual flow or vaginal bleeding


• nosebleeds


• paralysis


• prolonged bleeding from cuts


• red or black, tarry stools


• red or dark brown urine


• shortness of breath

Rare

• Cough


• fast heartbeat


• hives or welts


• itching skin


• noisy breathing


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• redness of the skin


• skin rash


• tightness in the chest


• unusual tiredness or weakness


• wheezing

Incidence not known

• Blue lips and fingernails


• blurred vision


• chest pain or discomfort


• confusion


• convulsions


• coughing that sometimes produces a pink frothy sputum


• difficult, fast, or noisy breathing, sometimes with wheezing


• fainting


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


• inability to speak


• increased sweating


• low blood pressure or pulse


• numbness or tingling in the face, arms, or legs


• pale skin


• severe or sudden headache


• severe or sudden weakness in the arm or leg on one side of the body


• slurred speech


• swelling in the legs and ankles


• trouble with walking or speaking


• unconsciousness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Kinlytic side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Kinlytic resources

• Kinlytic Side Effects (in more detail)
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• Kinlytic Drug Interactions
• Kinlytic Support Group
• 0 Reviews for Kinlytic - Add your own review/rating

• Kinlytic Prescribing Information (FDA)


• Kinlytic Concise Consumer Information (Cerner Multum)


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Triprolidine Syrup

Pronunciation: trye-PROE-li-deen
Generic Name: Triprolidine
Brand Name: Zymine

Triprolidine Syrup is used for:

Preventing or treating symptoms of hay fever and other upper respiratory allergies or the common cold, such as runny nose, sneezing, itching of the nose and throat, and itchy, watery eyes, and relieving cough. It may also be used for other conditions as determined by your doctor.

Triprolidine Syrup is an antihistamine. It works by blocking the action of histamine, reducing the symptoms of an allergic reaction.

Do NOT use Triprolidine Syrup if:

• you are allergic to any ingredient in Triprolidine Syrup or other similar medicines


• you are taking sodium oxybate (GHB)

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

Before using Triprolidine Syrup:

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

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


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


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


• if you have a fast, slow, or irregular heartbeat


• if you have a history of asthma; chronic obstructive pulmonary disease (COPD); chronic bronchitis; lung problems (eg, emphysema); shortness of breath; sleep apnea; heart blood vessel problems; stroke; seizures; a blockage of your stomach, intestine, or bladder; difficulty urinating; diabetes; ulcers; an enlarged prostate or other prostate problems; glaucoma; heart problems; high blood pressure; porphyria; phenylketonuria; or an overactive thyroid

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

• Sodium oxybate (GHB) because an increase in sleep duration and a decrease in the ability to breathe are likely to occur


• Monoamine oxidase (MAO) inhibitors (eg, phenelzine) because they may increase side effects of Triprolidine Syrup

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

How to use Triprolidine Syrup:

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

• Triprolidine Syrup may be taken with or without food.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.


• Use Triprolidine Syrup exactly as directed on the package, unless instructed differently by your doctor. If you are taking Triprolidine Syrup without a prescription, follow any warnings and precautions on the label.


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

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

Important safety information:

• Triprolidine Syrup may cause drowsiness or dizziness. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Triprolidine Syrup. Using Triprolidine Syrup alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• Avoid drinking alcohol or taking other medications that cause drowsiness (eg, sedatives, tranquilizers) while taking Triprolidine Syrup. Triprolidine Syrup will add to the effects of alcohol and other depressants. Ask your pharmacist if you have questions about which medicines are depressants.


• Triprolidine Syrup may cause dizziness. Alcohol, hot weather, exercise, and fever can increase this effect. To prevent it, sit up or stand slowly, especially in the morning. Also, sit or lie down at the first sign of dizziness.


• Do not become overheated in hot weather or during exercise or other activities since heatstroke may occur.


• If you are scheduled for allergy skin testing, do not take Triprolidine Syrup for several days before the test because it may decrease your response to the skin tests.


• Phenylketonuria patients - Triprolidine Syrup contains phenylalanine.


• If you are using Triprolidine Syrup for cough, cold, or allergy symptoms, stop use and contact your doctor if your symptoms do not improve within 7 days or are accompanied by fever.


• Use Triprolidine Syrup with caution in the ELDERLY because they may be more sensitive to its effects, especially dizziness, sedation, and lightheadedness upon standing.


• Safe use and instructions for use in CHILDREN differs according to the brand used. Talk to your doctor or pharmacist if you have any questions about the brand you are using.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, discuss with your doctor the benefits and risks of using Triprolidine Syrup during pregnancy. Triprolidine Syrup is excreted in breast milk. If you are or will be breast-feeding while you are using Triprolidine Syrup, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Triprolidine Syrup:

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:

Dizziness; drowsiness; dry mouth, throat, and nose; excitability; thickening of mucus in nose or throat.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); convulsions; fast heartbeat or pounding in the chest; decreased alertness; hallucinations; tremor; wheezing.

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. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch .

See also: Triprolidine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include coma; excitement; hallucinations; loss of consciousness; muscle twitching; seizures; tremor; weakness.

Proper storage of Triprolidine Syrup:

Store Triprolidine Syrup at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Triprolidine Syrup out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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Theo-24

theophylline anhydrous

Dosage Form: Extended-Release Capsules

Theo-24 Description

Theophylline

Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:

The molecular formula of anhydrous theophylline is C7H8N4O2 with a molecular weight of 180.17.

Theo-24® is available as capsules intended for oral administration, containing 100 mg, 200 mg, 300 mg, or 400 mg of anhydrous theophylline per capsule, in an extended-release formulation which allows a 24-hour dosing interval for appropriate patients.

Inactive ingredients are edible ink (which contains synthetic black iron oxide, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Yellow No. 6, D&C Yellow No. 10, FD&C Red No. 40), ethylcellulose, gelatin, pharmaceutical glaze, colloidal silicon dioxide, starch, sucrose, talc, titanium dioxide, and coloring agents: 100 mg-includes FD&C Yellow No. 6; 200 mg-FD&C Red No. 3 and D&C Yellow No. 10; 300 mg-FD&C Blue No. 1 and FD&C Red No. 40; 400 mg-FD&C Red No. 40 and D&C Red No. 28.

Theo-24® Extended-release capsules meet Drug Release Test 6 as published in the current USP monograph for Theophylline Extended-release Capsules.

Theo-24 - Clinical Pharmacology

Mechanism of Action

Theophylline has two distinct actions in the airways of patients with reversible obstruction: smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

Serum Concentration-Effect Relationship

Bronchodilation occurs over the serum theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum theophylline concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum theophylline concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics

Overview

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS, Laboratory Tests).

Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states.¶

Population Characteristics	Total body clearance* mean (range) †† (mL/kg/min)	Half-life Mean (range) †† (hr)
¶ For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples.
* Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics.
†† Reported range or estimated range (mean ± 2 SD) where actual range not reported.
† NR =not reported or not reported in a comparable format.
** Median
Note: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline.
Age
Premature neonates
postnatal age 3-15 days	0.29 (0.09-0.49)	30 (17-43)
postnatal age 25-57 days	0.64 (0.04-1.2)	20 (9.4-30.6)
Term infants
postnatal age 1-2 days	NR †	25.7 (25-26.5)
postnatal age 3-30 weeks	NR †	11 (6-29)
Children
1-4 years	1.7 (0.5-2.9)	3.4 (1.2-5.6)
4-12 years	1.6 (0.8-2.4)	NR †
13-15 years	0.9 (0.48-1.3)	NR †
6-17 years	1.4 (0.2-2.6)	3.7 (1.5-5.9)
Adults (16-60 years)
otherwise healthy
non-smoking asthmatics	0.65 (0.27-1.03)	8.7 (6.1-12.8)
Elderly (>60 years)
non-smokers with normal cardiac,
liver, and renal function	0.41 (0.21-0.61)	9.8 (1.6-18)
Concurrent illness or altered physiological state
Acute pulmonary edema	0.33**(0.07-2.45)	19**(3.1-82)
COPD >60 years, stable non-smoker >1 year	0.54 (0.44-0.64)	11 (9.4-12.6)
COPD with cor-pulmonale	0.48 (0.08-0.88)	NR †
Cystic fibrosis (14-28 years)	1.25 (0.31-2.2)	6.0 (1.8-10.2)
Fever associated with acute viral
respiratory illness (children 9-15 years)	NR †	7.0 (1.0-13)
Liver disease – cirrhosis	0.31**(0.1-0.7)	32**(10-56)
acute hepatitis	0.35 (0.25-0.45)	19.2 (16.6-21.8)
cholestasis	0.65 (0.25-1.45)	14.4 (5.7-31.8)
Pregnancy – 1st trimester	NR †	8.5 (3.1-13.9)
2nd trimester	NR †	8.8 (3.8-13.8)
3rd trimester	NR †	13.0 (8.4-17.6)
Sepsis with multi-organ failure	0.47 (0.19-1.9)	18.8 (6.3-24.1)
Thyroid disease – hypothyroid	0.38 (0.13-0.57)	11.6 (8.2-25)
hyperthyroid	0.8 (0.68-0.97)	4.5 (3.7-5.6)

Absorption

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single immediate-release dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2 hr after dose. Co-administration of theophylline with food or antacids does not cause clinically significant changes in the absorption of theophylline from immediate-release dosage forms.

Theo-24® capsules contain hundreds of coated beads of theophylline. Each bead is an individual extended-release delivery system. After dissolution of the capsules these beads are released and distributed in the gastrointestinal tract, thus minimizing the probability of high local concentrations of theophylline at any particular site.

In a 6-day multiple-dose study involving 18 subjects (with theophylline clearance rates between 0.57 and 1.02 mL/kg/min) who had fasted overnight and 2 hours after morning dosing, Theo-24® given once daily in a dose of 1500 mg produced serum theophylline levels that ranged between 5.7 mcg/mL and 22 mcg/mL. The mean minimum and maximum values were 11.6 mcg/mL and 18.1 mcg/mL, respectively, with an average peak-trough difference of 6.5 mcg/mL. The mean percent fluctuation [(Cmax–Cmin /Cmin) x 100] equals 80%. A 24-hour single-dose study demonstrated an approximately proportional increase in serum levels as the dose was increased from 600 to 1500 mg.

Taking Theo-24® with a high-fat-content meal may result in a significant increase in the peak serum level and in the extent of absorption of theophylline as compared to administration in the fasted state (see PRECAUTIONS, Drug/Food Interactions).

Following the single-dose administration (8 mg/kg) of Theo-24® to 20 normal subjects who had fasted overnight and 2 hours after morning dosing, peak serum theophylline concentrations of 4.8 ± 1.5 (SD) mcg/mL were obtained at 13.3 ± 4.7 (SD) hours. The amount of the dose absorbed was approximately 13% at 3 hours, 31% at 6 hours, 55% at 12 hours, 70% at 16 hours, and 88% at 24 hours. The extent of theophylline bioavailability from Theo-24® was comparable to the most widely used 12-hour extended-release product when both products were administered every 12 hours.

Distribution

Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva theophylline concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of theophylline, primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound + unbound) serum concentrations of theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased theophylline binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum theophylline concentration. Generally, concentrations of unbound theophylline should be maintained in the range of 6-12 mcg/mL.

Metabolism

Following oral dosing, theophylline does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations (see DOSAGE AND ADMINISTRATION, Table VI). Accurate prediction of dose-dependency of theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum theophylline concentration in response to dosage changes.

Excretion

In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, the large fraction of the theophylline dose excreted in the urine as unchanged theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline concentrations in neonates with reduced renal function (see WARNINGS).

Serum Concentrations at Steady State

After multiple doses of theophylline, steady state is reached in 30–65 hours (average 40 hours) in adults. At steady state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean theophylline half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid theophylline clearance. In patients with high theophylline clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum theophylline concentration may be only 30% of peak with a 6-hour dosing interval. In these patients a slow release formulation would allow a longer dosing interval (8-12 hours) with a smaller peak/trough difference.

Special Populations (See Table I for mean clearance and half-life values)

Geriatric

The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients (see WARNINGS).

Pediatrics

The clearance of theophylline is very low in neonates (see WARNINGS). Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum theophylline concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION).

Gender

Gender differences in theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.

Race

Pharmacokinetic differences in theophylline clearance due to race have not been studied.

Renal Insufficiency

Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, approximately 50% of the administered theophylline dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function (see WARNINGS).

Hepatic Insufficiency

Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function (see WARNINGS).

Congestive Heart Failure (CHF)

Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with CHF (see WARNINGS).

Smokers

Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking (see WARNINGS). Use of nicotine gum has been shown to have no effect on theophylline clearance.

Fever

Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of theophylline clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum theophylline concentrations. Children with rapid rates of theophylline clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum theophylline concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with sustained fever (see WARNINGS).

Miscellaneous

Other factors associated with decreased theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with any of these conditions (see WARNINGS). Other factors associated with increased theophylline clearance include hyperthyroidism and cystic fibrosis.

Clinical Studies

In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that theophylline decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta2 agonists. Theophylline has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.

In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.

Indications and Usage for Theo-24

Theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

Contraindications

Theo-24® is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

Warnings

Concurrent Illness

Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

 

Active peptic ulcer disease

 

Seizure disorders

 

Cardiac arrhythmias (not including bradyarrhythmias)

Conditions That Reduce Theophylline Clearance

There are several readily identifiable causes of reduced theophylline clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur. Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors:

Age

 

Neonates (term and premature)

 

Children <1 year

 

Elderly (>60 years)

Concurrent Diseases

 

Acute pulmonary edema

 

Congestive heart failure

 

Cor-pulmonale

 

Fever; ≥102° F for 24 hours or more; or lesser temperature elevations for longer periods

 

Hypothyroidism

 

Liver disease; cirrhosis, acute hepatitis

 

Reduced renal function in infants <3 months of age

 

Sepsis with multi-organ failure

 

Shock

Cessation of Smoking

Drug Interactions

Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin) (see PRECAUTIONS, Drug Interactions, Table II).

When Signs or Symptoms of Theophylline Toxicity Are Present

Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately. Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the healthcare professional may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI).

Dosage Increases

Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the theophylline dose on the basis of a low serum concentration, the healthcare professional should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests).

As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI).

Precautions

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy, prior to increases in theophylline dose, and during follow up (see WARNINGS). The dose of theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum theophylline concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION, Table V).

Monitoring Serum Theophylline Concentrations

Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows:

1. When initiating therapy to guide final dosage adjustment after titration.


2. Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.


3. Whenever signs or symptoms of theophylline toxicity are present.


4. Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter theophylline clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration; 12 hours after a dose at steady-state (expected peak serum theophylline concentration range is between 5 –15 mcg/mL). For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum theophylline concentration can be two or more times greater than the trough concentration with an extended-release formulation. If the serum sample is drawn more or less than twelve (12) hours after the dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of theophylline toxicity are present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the healthcare professional without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL

Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests

As a result of its pharmacological effects, theophylline at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 μEq/L to 800 μEq/L, total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of tri-iodothyronine (144 before, 131 after one week and 142 ng/dL after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.

Information for Patients

The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with theophylline, even if another cause is suspected. The patient should be instructed to contact their healthcare professional if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another healthcare professional adds a new medication or discontinues a previously prescribed medication. Patients should be informed that theophylline interacts with a wide variety of drugs (see Table II). The dietary supplement St. John’s Wort (Hypericum perforatum) should not be taken at the same time as theophylline, since it may result in decreased theophylline levels. If patients are already taking St. John’s Wort and theophylline together, they should consult their healthcare professional before stopping the St. John’s Wort, since their theophylline concentrations may rise when this is done, resulting in toxicity. Patients should be instructed to inform all healthcare professionals involved in their care that they are taking theophylline, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their healthcare professional. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Patients should be instructed to take this medication each morning at approximately the same time and not to exceed the prescribed dose.

Patients who require a relatively high dose of theophylline should be informed of important considerations relating to time of drug administration and meal content (see PRECAUTIONS, Drug/Food Interactions; and DOSAGE AND ADMINISTRATION).

Drug Interactions

Drug/Drug Interactions

Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs.

The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect ” column of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15% change in theophylline clearance).

The listing of drugs in Table II is current as of June 2004. The listing of drugs in Table III is current as of January 2, 1996. New interactions are continuously being reported for theophylline, especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with theophylline if it is not listed in Table II. Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported.

Table II. Clinically significant drug interactions with theophylline*.

Drug	Type of Interaction	Effect**
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic.	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects, possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.