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Wednesday, March 14, 2012

Nexavar

Generic Name: Sorafenib Tosylate
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide
Molecular Formula: C₂₁H₁₆ClF₃N₄O₃
CAS Number: 284461-73-0

Introduction

Antineoplastic agent; inhibitor of several serine/threonine and receptor tyrosine kinases.¹ ² ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ¹⁰ ¹¹ ¹² ¹³ ¹⁵ ¹⁶ ¹⁷

Uses for Nexavar

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma (designated an orphan drug by FDA for this use).¹ ³ ⁴ ⁵ ¹⁴ ¹⁵ ¹⁶ ¹⁷

Nexavar Dosage and Administration

General

Monitor BP weekly during the first 6 weeks of therapy; thereafter, monitor and treat, if required, in accordance with established medical practice.¹ (See Cardiovascular Effects under Cautions.)

Administration

Oral Administration

Administer ≥1 hour before or 2 hours after a meal, since administration with a high-fat meal may decrease oral bioavailability.¹

Dosage

Available as sorafenib tosylate; dosage expressed in terms of sorafenib.¹

Adults

Renal Cell Carcinoma

General Dosage

Oral

400 mg twice daily.¹ ² ⁴ ⁵ ¹⁵

Continue therapy for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.¹

Dosage Modification for Toxicity

Dosage may be reduced or therapy temporarily interrupted if adverse effects, such as cutaneous toxicity, occur.¹

If dosage reduction is necessary, dosage may be decreased to 400 mg once daily.¹ If further dosage reduction is required, dosage may be decreased to 400 mg every other day.¹

Suggested Dosage Modification for Cutaneous Toxicity 1
Cutaneous Toxicity Grade	Occurrence	Suggested Dosage Modification
Grade 1: numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema, and/or discomfort of the hands or feet that does not disrupt the patient’s normal activities	Any occurrence	Continue therapy with sorafenib and consider topical therapy for symptomatic relief
Grade 2: painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities	1^st occurrence	Continue therapy with sorafenib and consider topical therapy for symptomatic relief If improvement is not evident within 7 days, see below
	No improvement within 7 days or 2^nd or 3^rd occurrence	Interrupt sorafenib therapy until toxicity resolves to grade 0 or 1 When resuming therapy, decrease sorafenib dosage by one dose level (e.g., to 400 mg once daily or 400 mg every other day)
	4^th occurrence	Discontinue sorafenib therapy
Grade 3: moist desquamation, ulceration, blistering or severe pain of the hands or feet, and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living	1^st or 2^nd occurrence	Interrupt sorafenib therapy until toxicity resolves to grade 0 or 1 When resuming therapy, decrease sorafenib dosage by one dose level (e.g., to 400 mg once daily or 400 mg every other day)
	3^rd occurrence	Discontinue sorafenib therapy

Prescribing Limits

Adults

Renal Cell Carcinoma

Oral

Highest dosage evaluated clinically was 800 mg twice daily.¹

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild or moderate (Child-Pugh class A or B) hepatic impairment.¹ Not studied in patients with severe (Child-Pugh class C) hepatic impairment.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations for patients with renal impairment.¹ ¹⁴ (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustment is required on the basis of patient age.¹ (See Geriatric Use under Cautions.)

Cautions for Nexavar

Contraindications

Known hypersensitivity to sorafenib or any ingredient in the formulation.¹

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality.

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.¹

Pregnancy should be avoided during and for ≥2 weeks following completion of therapy.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹ (See Advice to Patients.)

Major Toxicities

Dermatologic Effects

Palmar-plantar erythrodysesthesia (i.e., hand-foot syndrome) and rash occur frequently.¹ ² ⁴ ⁵ ⁸ ⁹ ¹⁰ ¹¹ ¹² ¹⁵

Reactions (generally grade 1 or 2) typically appear during the first 6 weeks of therapy.¹ ¹⁵

Management includes topical symptomatic therapy, temporary interruption of therapy, and/or dosage modification; consider permanent discontinuance of therapy in severe or persistent cases.¹

Cardiovascular Effects

Mild or moderate treatment-emergent hypertension reported early in the course of treatment;¹ ² ⁴ ⁵ ⁶ ⁸ ⁹ ¹⁰ ¹¹ ¹² ¹⁵ ¹⁷ generally managed with standard antihypertensive therapy.¹ ¹² ¹⁵ (See General under Dosage and Administration.)

If hypertension is severe or persistent despite use of antihypertensive therapy, consider temporary or permanent discontinuance of sorafenib.¹

Treatment-emergent cardiac ischemia or infarction reported; consider temporary or permanent discontinuance of therapy if cardiac ischemia and/or infarction occurs.¹

GI Perforation

GI perforation, sometimes associated with intra-abdominal tumor, reported rarely; discontinue therapy if GI perforation occurs.¹

Hemorrhage

Increased risk of bleeding;¹ ¹⁵ consider permanent discontinuance of therapy if any bleeding episode requiring medical attention occurs.¹

Monitor patients receiving concomitant therapy with warfarin and sorafenib for increased risk of bleeding episodes or INR elevations.¹ Assess for changes in PT or INR regularly and monitor for clinical bleeding episodes.¹

General Precautions

Japanese Populations

Reduction in systemic exposure to sorafenib reported in Japanese patients (see Special Populations under Pharmacokinetics); clinical importance is not known.¹

Wound-healing Complications

Effect on wound healing not established; manufacturer recommends that therapy be temporarily interrupted in patients undergoing major surgery.¹ Decision to resume therapy should be based on clinical assessment of adequacy of wound healing.¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Discontinue nursing because of potential risk to nursing infants.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹ ¹⁴

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Hepatic Impairment

Systemic exposure and safety data in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) similar to these data in patients without hepatic impairment.¹ ¹⁴ Safety and efficacy not established in patients with severe (Child-Pugh class C) hepatic impairment.¹

Renal Impairment

Systemic exposure data in patients with mild or moderate renal impairment (Cl_cr 30–80 mL/minute) similar to such data in patients without renal impairment.¹ Safety and efficacy not established in patients with severe renal impairment (Cl_cr <30 mL/minute) or in those undergoing peritoneal dialysis or hemodialysis.¹ ¹⁴

Common Adverse Effects

Hypophosphatemia,¹ ¹⁵ diarrhea,¹ ¹⁰ ¹⁵ increased lipase concentrations,¹ ¹⁵ rash/desquamation,¹ ¹⁵ fatigue,¹ ¹⁰ ¹⁵ hand-foot syndrome,¹ ¹⁰ ¹⁵ increased amylase concentrations,¹ alopecia,¹ ¹⁵ nausea,¹ ¹⁵ lymphopenia,¹ ¹⁵ pruritus,¹ ¹⁵ neutropenia,¹ hypertension,¹ ¹⁰ ¹⁵ anorexia,¹ ¹⁵ vomiting,¹ ¹⁵ constipation,¹ ¹⁵ hemorrhage (all sites, including GI and respiratory tract),¹ ¹⁵ dyspnea,¹ ¹⁵ cough,¹ ¹⁵ sensory neuropathy,¹ ¹⁵ dry skin,¹ pain (abdominal, joint, headache, mouth, bone, and tumor),¹ ¹⁵ weight loss,¹ ¹⁵ erythema,¹ asthenia,¹ leukopenia.¹

Interactions for Nexavar

Metabolized by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A9.¹ ⁷

Inhibits CYP isoenzymes 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 in vitro.¹ Unlikely to induce CYP1A2 or CYP3A4.¹

Inhibits glucuronidation by UGT1A1 and UGT1A9.¹

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Unlikely to alter metabolism of sorafenib based on drug interaction studies with ketoconazole.¹

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of sorafenib).¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 2C19, 2D6, or 3A4: Pharmacokinetic interaction (alteration of substrate metabolism) unlikely.¹

Substrates of CYP2B6 or CYP2C8: Possible pharmacokinetic interaction (increased systemic exposure to the substrate); caution is advised during concomitant use.¹

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase

Substrates of UGT1A1 or UGT1A9: Potential pharmacokinetic interaction (increased systemic exposure to the substrate).¹ Caution is advised with concomitant use of sorafenib and substrates of UGT1A1 (e.g., irinotecan).¹

Specific Drugs

Drug	Interaction	Comments
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Possible decreased plasma sorafenib concentrations¹
Dexamethasone	Possible decreased plasma sorafenib concentrations¹
Dextromethorphan	Pharmacokinetic interaction unlikely¹
Doxorubicin	Possible increased AUC of doxorubicin¹	Caution is advised¹
Gemcitabine	Sorafenib does not appear to affect gemcitabine pharmacokinetics¹
Irinotecan	Possible increased AUC of irinotecan and its active metabolite, SN-38¹	Caution is advised¹
Ketoconazole	Pharmacokinetic interaction unlikely ¹
Midazolam	Pharmacokinetic interaction unlikely¹
Omeprazole	Pharmacokinetic interaction unlikely¹
Oxaliplatin	Sorafenib does not appear to affect oxaliplatin pharmacokinetics¹
Rifampin	Possible decreased plasma sorafenib concentrations¹
St. John's wort (Hypericum perforatum)	Possible decreased plasma sorafenib concentrations¹
Warfarin	Increased risk of bleeding episodes or INR elevations; sorafenib does not appear to affect warfarin metabolism¹	Monitor regularly for changes in PT or INR and for clinical bleeding episodes¹

Nexavar Pharmacokinetics

Absorption

Bioavailability

Mean relative bioavailability is 38–49% when compared with oral solution.¹ Peak plasma concentrations attained in approximately 3 hours.¹

Food

High-fat meal reduces bioavailability by about 29%.¹

Special Populations

AUC in Japanese patients receiving sorafenib 400 mg twice daily reduced by 45% compared with data from phase 1 studies in Caucasian patients.¹ (See Japanese Populations under Cautions.)

Distribution

Extent

Not known whether sorafenib is distributed into milk.¹

Plasma Protein Binding

99.5%.¹

Elimination

Metabolism

Metabolized mainly in the liver via oxidation by CYP3A4 and glucuronidation by UGT1A9.¹ ⁷

At least 8 metabolites identified.¹ The main circulating metabolite, a pyridine N-oxide derivative, is pharmacologically active and accounts for approximately 9–16% of total plasma concentrations of the drug.¹

Elimination Route

Excreted in feces (77%) and urine (19%).¹

51% of a dose recovered in feces as unchanged drug; unchanged drug not recovered in urine.¹

Half-life

Approximately 25–48 hours.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹ Store in a dry place.¹

ActionsActions

Mechanism of action not fully elucidated; appears to inhibit signal transduction pathways involving multiple intracellular (e.g., c-Raf, b-Raf, mutant b-Raf) and cell surface kinases (e.g., c-Kit, Flt-3, vascular endothelial growth factor receptors 2 and 3, platelet-derived growth factor receptor-β) in vitro.¹ ² ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ¹⁰ ¹¹ ¹² ¹³ ¹⁵ ¹⁶ ¹⁷

Advice to Patients

Importance of reading the manufacturer’s patient information prior to beginning therapy and rereading it each time the prescription is renewed.¹

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Necessity of advising women to avoid pregnancy during therapy and for ≥2 weeks following completion of sorafenib therapy, as well as advising women to discontinue nursing while receiving therapy.¹ Necessity of advising women and men to use effective contraceptive methods during sorafenib therapy and for ≥2 weeks following completion of therapy.¹ Advise women of the potential risk to the fetus (e.g., birth defects) and/or the potential risk for loss of the pregnancy.¹

Risk of hand-foot syndrome and rash.¹ Importance of advising patient about appropriate countermeasures.¹

Risk of hypertension, particularly during the first 6 weeks of sorafenib therapy.¹ Importance of monitoring BP regularly during therapy.¹

Risk of bleeding.¹ Importance of patients promptly informing clinicians of any episodes of bleeding.¹

Risk of potential GI perforation.¹

Risk of potential cardiac ischemia and/or infarction.¹ Importance of patients immediately informing clinicians of any episodes of chest pain or other symptoms of cardiac ischemia and/or infarction.¹

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

Importance of informing 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.

Sorafenib Tosylate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	200 mg (of sorafenib)	Nexavar	Bayer , (comarketed by Onyx)

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 November 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Bayer. Nexavar (sorafenib tosylate) tablets prescribing information. West Haven, CT: 2007 Feb.

2. Ahmad T, Eisen T. Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin Cancer Res. 2004; 10:6388S-92S. [PubMed 15448036]

3. Food and Drug Administration. Cumulative list of all orphan designated products that have received marketing approval. Available at: . Accessed 2006 Feb 10.

4. Escudier B, Szczylik C, Eisen T et al. Randomized phase III trial of the raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Presented at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO). Orlando, FL. 2005 13–17 May. Abstract LBA 4510.

5. Ratain MJ, Eisen T, Stadler WM et al. Final findings from a phase II, placebo-controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Presented at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO). Orlando, FL. 2005 13–17 May. Abstract LBA 4544.

6. Favaro JP, George DJ. Targeted therapy in renal cell carcinoma. Expert Opin Investig Drugs. 2005; 14:1251-8. [PubMed 16185167]

7. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005; 23:6771-90. [IDIS 543417] [PubMed 16170185]

8. Cooney MM, Remick SC, Vogelzang NJ. Promising systemic therapy for renal cell carcinoma. Curr Treat Options Oncol. 2005; 6:357-65. [PubMed 16107239]

9. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005; 315:971-9. [PubMed 16002463]

10. Schöffski P, Dumez H, Clement P et al. Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. Ann Oncol . 2006 (Advance access [doi:10.1093/annonc/mdj133]); :.

11. Zakarija A, Soff G. Update on angiogenesis inhibitors. Curr Opin Oncol. 2005; 17:578-83. [PubMed 16224236]

12. Gollob JA. Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma. Clin Genitourin Cancer. 2005; 4:167-74. [PubMed 16425993]

13. Wilhelm SM, Carter C, Tang L et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004; 64:7099-109. [PubMed 15466206]

14. Bayer, West Haven, CT: Personal communication.

15. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007; 356:125-34. [PubMed 17215530]

16. Brugarolas J. Renal-cell carcinoma—molecular pathways and therapies. N Engl J Med. 2007; 356:185-7. [PubMed 17215538]

17. Govindarajan R, Adusumilli J, Baxter DL et al. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43-9006. J Clin Oncol. 2006; 24:e48. [PubMed 17008686]

More Nexavar resources

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

Nexavar Prescribing Information (FDA)

Nexavar Consumer Overview

Nexavar Advanced Consumer (Micromedex) - Includes Dosage Information

Nexavar MedFacts Consumer Leaflet (Wolters Kluwer)

Sorafenib Professional Patient Advice (Wolters Kluwer)

Compare Nexavar with other medications

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Tuesday, March 13, 2012

Triac

Generic Name: chlorpheniramine and phenylpropanolamine (klor feh NEER a meen and feh nill proe pa NO la meen)

Brand Names: A.R.M. Allergy Relief, Allerest 12 Hour, Chlornade, Condrin, Contac 12 Hour, Decongex-3, Demazin, Dura-Vent/A, Equi-Nade, Genamin, Gencold, Histade, Or-Phen-Ade, Ordrine, Ornade Spansules, Resaid, Rescon Liquid, Rhinolar-EX, Teldrin, Triac, Triaminic, Vanex Forte-R

What is Triac (chlorpheniramine and phenylpropanolamine)?

Chlorpheniramine is an antihistamine. It blocks the effects of the naturally occurring chemical histamine in the body. Chlorpheniramine prevents sneezing; itchy, watery eyes and nose; and other symptoms of allergies and hay fever.

Phenylpropanolamine is a decongestant. It constricts (shrinks) blood vessels (veins and arteries). This reduces the blood flow to certain areas and allows nasal passages to open up.

Chlorpheniramine and phenylpropanolamine is used to treat nasal congestion and sinusitis (inflammation of the sinuses) associated with allergies, hay fever, and the common cold.

Phenylpropanolamine, an ingredient in this product, has been associated with an increased risk of hemorrhagic stroke (bleeding into the brain or into tissue surrounding the brain) in women. Men may also be at risk. Although the risk of hemorrhagic stroke is low, the U.S. Food and Drug Administration (FDA) recommends that consumers not use any products that contain phenylpropanolamine.

Chlorpheniramine and phenylpropanolamine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Triac (chlorpheniramine and phenylpropanolamine)?

Use caution when driving, operating machinery, or performing other hazardous activities. Chlorpheniramine and phenylpropanolamine may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while taking chlorpheniramine and phenylpropanolamine.

Do not take more of this medication than is recommended. If your symptoms do not improve, or if they worsen, talk to your doctor.

Who should not take Triac (chlorpheniramine and phenylpropanolamine)?

Do not take chlorpheniramine and phenylpropanolamine if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Before taking this medication, tell your doctor if you have

kidney disease,

liver disease,

diabetes,

glaucoma,

any type of heart disease or high blood pressure,

thyroid disease,

emphysema or chronic bronchitis, or

difficulty urinating or an enlarged prostate.

You may not be able to take chlorpheniramine and phenylpropanolamine, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Chlorpheniramine and phenylpropanolamine is in the FDA pregnancy category B. This means that it is unlikely to harm an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant. This medication passes into breast milk and may harm a nursing baby. Do not take this medication without first talking to your doctor if you are breast-feeding a baby. If you are over 65 years of age, you may be more likely to experience side effects from chlorpheniramine and phenylpropanolamine. You may require a lower dose of this medication. Read the package label for directions or consult your doctor or pharmacist before treating a child with this medication. Children are more susceptible than adults to the effects of medicines and may have unusual reactions.

How should I take Triac (chlorpheniramine and phenylpropanolamine)?

Take chlorpheniramine and phenylpropanolamine exactly as directed. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water. Do not crush, chew, or break the long-acting or sustained-release forms of this medication. Swallow them whole. If you are unsure of the formulation of your medicine, ask your pharmacist for help.

If you cannot swallow the tablets or capsules, look for a liquid form of the medication.

To ensure that you get a correct dose, measure the liquid forms of chlorpheniramine and phenylpropanolamine with a special dose-measuring spoon or cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.

Do not take more of this medication than is recommended. An overdose of this medication can cause serious harm.

Do not take chlorpheniramine and phenylpropanolamine for longer than 7 days in a row. If your symptoms do not improve, if they get worse, or if you have a fever, talk to your doctor.

Store chlorpheniramine and phenylpropanolamine at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of a chlorpheniramine and phenylpropanolamine overdose include a dry mouth, large pupils, flushing, nausea, and vomiting.

What should I avoid while taking Triac (chlorpheniramine and phenylpropanolamine)?

Chlorpheniramine and phenylpropanolamine may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, other antihistamines, pain relievers, anxiety medicines, seizure medicines, and muscle relaxants. Dangerous sedation, dizziness, or drowsiness may occur if chlorpheniramine and phenylpropanolamine is taken with any of these medications.

Triac (chlorpheniramine and phenylpropanolamine) side effects

Serious side effects are unlikely to occur. Stop taking chlorpheniramine and phenylpropanolamine and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives).

Other, less serious side effects may be more likely to occur. Continue to take chlorpheniramine and phenylpropanolamine and talk to your doctor or try another similar medication if you experience

dryness of the eyes, nose, and mouth;

drowsiness or dizziness;

blurred vision;

difficulty urinating; or

excitation in children.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect Triac (chlorpheniramine and phenylpropanolamine)?

Do not take other over-the-counter cough, cold, allergy, diet, or sleep aids while taking chlorpheniramine and phenylpropanolamine without first talking to your doctor or pharmacist. Other medications may also contain chlorpheniramine, phenylpropanolamine, or other similar drugs. You may accidentally take too much of these medicines.

Drugs other than those listed here may also interact with chlorpheniramine and phenylpropanolamine. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

More Triac resources

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

Triaminic Consumer Overview

Compare Triac with other medications

Cold Symptoms
Cough and Nasal Congestion
Hay Fever
Sinusitis
Upper Respiratory Tract Infection

Where can I get more information?

Your pharmacist has additional information about chlorpheniramine and phenylpropanolamine written for health professionals that you may read.

What does my medication look like?

Many formulations of chlorpheniramine and phenylpropanolamine are available both over-the-counter and with a prescription. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

See also: Triac side effects (in more detail)

TetraVisc Forte

Generic Name: tetracaine (Ophthalmic route)

TE-tra-kane

Commonly used brand name(s)

In the U.S.

Altacaine

Tetcaine

TetraVisc

TetraVisc Forte

Available Dosage Forms:

Solution

Ointment

Therapeutic Class: Anesthetic, Local

Chemical Class: Amino Ester

Uses For TetraVisc Forte

Tetracaine eye drops are used to numb the eye before surgery, certain tests, or procedures. The eye drops are used to prevent pain during the procedure.

Tetracaine belongs to the group of medicines called local anesthetics. It works by blocking the pain signals at the nerve endings in the eye.

This medicine is to be administered only by or under the direct supervision of an eye doctor.

Before Using TetraVisc Forte

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 tetracaine eye drops 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 tetracaine eye drops in geriatric patients.

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are 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.

Hyaluronidase

St John's Wort

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.

Proper Use of tetracaine

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

A nurse or other trained health professional will give you this medicine. The eye drops are placed directly in the eye.

Precautions While Using TetraVisc Forte

Your doctor will check your progress closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it.

It is very important to protect your eye from injury while it is still numb. Do not touch or rub the eye. Do not use additional eye drops in the eye until your doctor tells you to. Protect your eye from dust particles, sand, or anything that might cause irritation.

TetraVisc Forte 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:

Rare

Blurred vision

redness of the clear part of the eye

sensitivity to light

severe stinging in the eye

tearing

throbbing eye pain

Incidence not known

Bloody eye

burning, stinging, itching, redness, or irritation of the eye

change in vision

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.

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Sunday, March 11, 2012

Triamcinolone Aerosol Solution

Pronunciation: TRYE-am-SIHN-oh lohn
Generic Name: Triamcinolone
Brand Name: Kenalog

Triamcinolone Aerosol Solution is used for:

Reducing itching, redness, and swelling associated with many skin conditions.

Triamcinolone Aerosol Solution is a corticosteroid. The exact way that it acts against most causes of inflammation is not known, but it is thought to slow or stop the chemicals in the body that cause the inflammation (eg, redness, swelling, irritation).

Do NOT use Triamcinolone Aerosol Solution if:

you are allergic to any ingredient in Triamcinolone Aerosol Solution

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

Before using Triamcinolone Aerosol Solution:

Some medical conditions may interact with Triamcinolone Aerosol Solution. 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 any kind of skin infection, cuts, scrapes, thinning of the skin, or lessened blood flow to your skin

if you have measles, tuberculosis (TB), a positive TB skin test, chickenpox, shingles, or have recently had a vaccination

if you are taking an oral corticosteroid (eg, prednisone)

Some MEDICINES MAY INTERACT with Triamcinolone Aerosol Solution. Because little, if any, of Triamcinolone Aerosol Solution is absorbed into the blood, the risk of it interacting with another medicine is low.

Ask your health care provider if Triamcinolone Aerosol Solution 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 Triamcinolone Aerosol Solution:

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

Wash your hands immediately after using Triamcinolone Aerosol Solution, unless your hands are part of the treated area.

Shake well before each use. Hold the container 3 to 6 inches (8 to 15 cm) from the infected area and spray lightly.

Do not apply Triamcinolone Aerosol Solution on the underarms or groin areas unless directed to do so by your doctor.

Do not wrap or otherwise cover the treated area with bandages or wear tight-fitting clothing unless specifically directed by your doctor. Do not use tight-fitting diapers or plastic pants on children using Triamcinolone Aerosol Solution in the diaper area.

If you miss a dose of Triamcinolone Aerosol Solution, use 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.

Ask your health care provider any questions you may have about how to use Triamcinolone Aerosol Solution.

Important safety information:

Triamcinolone Aerosol Solution is for external use only. If you get Triamcinolone Aerosol Solution in your eyes, immediately flush with cool tap water.

Do not inhale any of Triamcinolone Aerosol Solution.

Do NOT use more than the recommended dose, use for longer than prescribed, or use over a large area of the body without checking with your doctor.

Serious side effects may occur if too much of Triamcinolone Aerosol Solution is absorbed through the skin. This may be more likely to occur if you use Triamcinolone Aerosol Solution over a large area of the body or for a prolonged period of time. It may also be more likely if you wrap or bandage the area after you apply Triamcinolone Aerosol Solution. The risk is greater in children. Do not use more than the prescribed dose. Contact your doctor right away if you develop unusual weight gain (especially in the face), muscle weakness, increased thirst or urination, confusion, unusual drowsiness, severe or persistent headache, fever, or vision changes. Discuss any questions or concerns with your doctor.

If your symptoms do not get better within 2 weeks or if they get worse, check with your doctor.

Talk with your doctor before you use any other medicines or cleansers on your skin.

Do not use Triamcinolone Aerosol Solution for other skin conditions at a later time.

Tell your doctor or dentist that you use Triamcinolone Aerosol Solution before you receive any medical or dental care, emergency care, or surgery.

Triamcinolone Aerosol Solution has a corticosteroid in it. Before you start any new medicine, check the label to see if it has a corticosteroid in it too. If it does or if you are not sure, check with your doctor or pharmacist.

Triamcinolone Aerosol Solution is flammable. Do not apply near heat, an open flame, or while smoking.

Corticosteroids may affect growth rate in CHILDREN and teenagers in some cases. They may need regular growth checks while they use Triamcinolone Aerosol Solution.

Triamcinolone Aerosol Solution should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.

PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Triamcinolone Aerosol Solution while you are pregnant. It is not known if Triamcinolone Aerosol Solution is found in breast milk after topical use. If you are or will be breast-feeding while you use Triamcinolone Aerosol Solution, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Triamcinolone Aerosol Solution:

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:

Mild, temporary stinging.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); acne-like rash; excessive hair growth; impaired wound healing; inflamed hair follicles; inflammation around the mouth; severe or persistent itching, burning, dryness, redness, or swelling of the skin; thinning, softening, or discoloration of the skin.

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

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Triamcinolone Aerosol Solution may be harmful if swallowed.

Proper storage of Triamcinolone Aerosol Solution:

Store Triamcinolone Aerosol Solution at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Store away from heat and direct sunlight. Do not puncture, break, or burn the canister even if it appears to be empty. Keep Triamcinolone Aerosol Solution out of the reach of children and away from pets.

General information:

If you have any questions about Triamcinolone Aerosol Solution, please talk with your doctor, pharmacist, or other health care provider.

Triamcinolone Aerosol Solution 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 Triamcinolone Aerosol Solution. 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

More Triamcinolone resources

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Wednesday, March 7, 2012

Theophylline in Dextrose

Generic Name: theophylline, anhydrous and dextrose

Dosage Form: injection, solution
Theophylline in 5% Dextrose Injections USP

Do not admix with other drugs.

Theophylline in Dextrose Description

Theophylline in 5% Dextrose Injections USP are sterile, nonpyrogenic solutions intended for intravenous administration, prepared from theophylline and dextrose in Water for Injection USP.

Composition - Each 100 mL contains:
Solution	Anhydrous Thephylline USP	Hydrous Dextrose USP	pH	Calculated Osmolarity mOsmol/liter
Water for Injection USP, qs
0.08% Theophylline in 5% Dextrose Injection USP	80 mg	5 g	4.7 (3.5–6.5)	255
0.16% Theophylline in 5% Dextrose Injection USP	160 mg	5 g	4.7 (3.5–6.5)	260

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 formulas of the active ingredients are:

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

The molecular formula of hydrous dextrose is C6H12O6•H2O with a molecular weight of 198.17.

The EXCEL® Container is Latex-free; PVC-free; and DEHP-free.

The plastic container is made from a multilayered film specifically developed for parenteral drugs. It contains no plasticizers and exhibits virtually no leachables. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is nontoxic and biologically inert. The container-solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary.

The closure system has two ports; the one for the administration set has a tamper evident plastic protector. Refer to the Directions for Use of the container.

Theophylline in Dextrose - 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 bronchodilatation 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 and pulmonary function has been found in most studies to require serum theophylline concentrations greater than 10 mcg/mL. At serum theophylline concentrations greater than 20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining average 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

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 receiving intravenous theophylline (e.g., at 24-hr intervals). More frequent measurements should be made during the initiation of therapy and 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 less than 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
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 (greater than 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- greater than 60 years, stable
non-smoker greater than 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)

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.

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

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 less than 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 less than 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 greater than 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

In a patient who has received no theophylline in the previous 24 hours, a loading dose of intravenous theophylline of 4.6 mg/kg, calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum post-distribution serum concentration of 10 mcg/mL with a range of 6–16 mcg/mL. In non-smoking adults, initiation of a constant intravenous theophylline infusion of 0.4 mg/kg/hr at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7–26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg theophylline followed by a constant intravenous infusion of 0.8 mg/kg/hr. (See DOSAGE AND ADMINISTRATION.)

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 (greater than 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 greater than 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. 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

Inhaled beta-2 selective agonists and systemically administered corticosteroids are the treatments of first choice for management of acute exacerbations of asthma. The results of controlled clinical trials on the efficacy of adding intravenous theophylline to inhaled beta-2 selective agonists and systemically administered corticosteroids in the management of acute exacerbations of asthma have been conflicting. Most studies in patients treated for acute asthma exacerbations in an emergency department have shown that addition of intravenous theophylline does not produce greater bronchodilation and increases the risk of adverse effects. In contrast, other studies have shown that addition of intravenous theophylline is beneficial in the treatment of acute asthma exacerbations in patients requiring hospitalization, particularly in patients who are not responding adequately to inhaled beta-2 selective agonists.

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 Theophylline in Dextrose

Theophylline in 5% Dextrose Injections USP are indicated as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids for the treatment of acute exacerbations of the symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

Contraindications

Theophylline in 5% Dextrose Injections USP are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

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 infusion rate 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 less than 1 year

    Elderly (greater than 60 years)

  Concurrent Diseases

    Acute pulmonary edema

    Congestive heart failure

    Cor-pulmonale

    Fever; greater than or equal to 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 less than 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), the intravenous infusion should be stopped and a serum theophylline concentration measured immediately.

Dosage Increases

Increases in the dose of intravenous theophylline should not be made in response to an acute exacerbation of symptoms unless the steady-state serum theophylline concentration is less than 10 mcg/mL.

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 infusion rate increases to about 25% of the previous infusion rate will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION, Table VI ).

Solutions containing dextrose without electrolytes should not be administered simultaneously with blood through the same infusion set because of the possibility of agglomeration of erythrocytes.

The intravenous administration of these solutions may cause fluid overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema.

Because dosages of these drugs are titrated to response (see DOSAGE AND ADMINISTRATION), no additives should be made to Theophylline in 5% Dextrose Injection USP.

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 and prior to increases in theophylline dose (see WARNINGS).

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:

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

Whenever signs or symptoms of theophylline toxicity are present.

Whenever there is a new illness, worsening of an existing concurrent illness or a change in the patient's treatment regimen that may alter theophylline clearance (e.g., fever greater than 102°F sustained for greater than or equal to 24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

In patients who have received no theophylline in the previous 24 hours, a serum concentration should be measured 30 minutes after completion of the intravenous loading dose to determine whether the serum concentration is less than 10 mcg/mL indicating the need for an additional loading dose or greater than 20 mcg/mL indicating the need to delay starting the constant IV infusion. Once the infusion has begun, a second measurement should be obtained after one expected half life (e.g., approximately 4 hours in children age 1 to 9 years and 8 hours in non-smoking adults; see Table I for the expected half life in additional patient populations). The second measurement should be compared to the first to determine the direction in which the serum concentration has changed. The infusion rate can then be adjusted before steady state is reached in an attempt to prevent an excessive or sub-therapeutic theophylline concentration from being achieved.

If a patient has received theophylline in the previous 24 hours, the serum concentration should be measured before administering an intravenous loading dose to make sure that it is safe to do so. If a loading dose is not indicated (i.e., the serum theophylline concentration is greater than or equal to 10 mcg/mL), a second measurement should be obtained as above at the appropriate time after starting the intravenous infusion. If, on the other hand, a loading dose is indicated (see DOSAGE AND ADMINISTRATION for guidance on selection of the appropriate loading dose), a second blood sample should be obtained after the loading dose and a third sample should be obtained one expected half-life after starting the constant infusion to determine the direction in which the serum concentration has changed.

Once the above procedures related to initiation of intravenous theophylline infusion have been completed, subsequent serum samples for determination of theophylline concentration should be obtained at 24-hour intervals for the duration of the infusion. The theophylline infusion rate should be increased or decreased as appropriate based on the serum theophylline levels.

When signs or symptoms of theophylline toxicity are present, the intravenous infusion should be stopped and a serum sample for theophylline concentration should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician 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.

Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged therapy or whenever the condition of the patient warrants such evaluation.

Do not use plastic container in series connection.

If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. If administration is not controlled by a pumping device, refrain from applying excessive pressure (greater than 300mmHg) causing distortion to the container such as wringing or twisting. Such handling could result in breakage of the container.

These solutions are intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours.

Use only if solution is clear and container and seals are intact.

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 triiodothyronine (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.

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., less than 15% change in theophylline clearance).

The listing of drugs in Tables II and III are current as of September 1, 1995. New interactions are continuously being reported for theophylline, especially with new chemical entities. The clinician 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 greater than or equal to 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.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20–40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar