Erlotinib

Class: Antineoplastic Agents
Chemical Name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-quinazolinamine hydrochloride
Molecular Formula: C₂₂H₂₃N₃O₄•HCl
CAS Number: 183319-69-9
Brands: Tarceva

Introduction

Antineoplastic agent; a kinase inhibitor.¹

Uses for Erlotinib

Non-small Cell Lung Cancer

Treatment of locally advanced or metastatic non-small cell lung cancer that is refractory to at least one prior chemotherapy regimen.¹

Combination regimen of erlotinib with carboplatin and paclitaxel or with gemcitabine and cisplatin not effective as first-line therapy† for the treatment of locally advanced or metastatic non-small cell lung cancer;^{1 4 5} use in this setting not recommended.¹

Pancreatic Cancer

Used in combination with gemcitabine for first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer.¹

Erlotinib Dosage and Administration

Administration

Oral Administration

Administer orally once daily, at least 1 hour before or 2 hours after ingestion of food.¹

Dosage

Available as erlotinib hydrochloride; dosage expressed in terms of erlotinib.¹

Adults

Non-small Cell Lung Cancer

Second-line or Subsequent Treatment of Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Oral

150 mg once daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs; once disease progression occurs, there is no evidence that continued therapy is beneficial.¹ In principal efficacy study, therapy was continued for a median of 9.6 weeks.²

Pancreatic Cancer

First-line Therapy of Locally Advanced, Unresectable or Metastatic Pancreatic Cancer

Oral

100 mg once daily, in combination with gemcitabine (1 g/m² IV once weekly [for 7 consecutive weeks of an 8-week cycle and thereafter for 3 consecutive weeks of a 4-week cycle]).¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Dosage Modification for Toxicity

When dosage reduction is required, reduce dosage in 50-mg decrements.¹

Pulmonary Toxicity

Interrupt therapy pending diagnostic evaluation upon acute onset of new or progressive pulmonary manifestations.¹ Discontinue if interstitial lung disease is diagnosed.¹ (See Pulmonary Toxicity under Cautions.)

Dehydration and/or Renal Toxicity

Interrupt therapy and take appropriate measures to intensively rehydrate patient if dehydration occurs, particularly in patients at risk for renal failure.¹ (See Renal Failure under Cautions.)

Hepatic Toxicity

Consider interruption of therapy or dosage reduction with frequent monitoring of liver function tests if worsening of liver function test results occurs; consider such action before severe changes in test results occur.¹

Interrupt or discontinue therapy if severe changes in liver function test results occur in patients with normal hepatic function prior to treatment.^{1 8} (See Hepatic Toxicity under Cautions.)

Discontinue therapy if hepatic failure occurs.¹

GI Toxicity

Permanently discontinue therapy if GI perforation occurs.^{1 10}

Consider dosage reduction or temporary interruption of therapy if severe diarrhea (unresponsive to loperamide or resulting in dehydration) occurs.¹

Dermatologic Toxicity

Interrupt or discontinue therapy if severe bullous, blistering, or exfoliative reaction occurs.^{1 10}

Ocular Toxicity

Interrupt or discontinue therapy if acute or worsening ocular toxicity (e.g., eye pain) occurs.^{1 10}

Special Populations

Hepatic Impairment

Consider interruption or discontinuance of therapy if severe adverse effects occur.¹ (See Hepatic Impairment under Cautions.)

Geriatric Patients

No dosage adjustment required.¹

Cautions for Erlotinib

Contraindications

• 
  

  No known contraindications according to manufacturer.¹

  
  

Warnings/Precautions

Pulmonary Toxicity

Serious, sometimes fatal, interstitial lung disease-like events reported, usually developing between 5 days to >9 months (median: 39 days) after initiating therapy.¹ Often associated with concomitant or prior chemotherapy, prior radiotherapy, preexisting parenchymal lung disease, metastatic lung disease, or pulmonary infections.¹

If acute onset of new or progressive pulmonary manifestations (e.g., dyspnea, cough, fever) occurs, interrupt therapy pending diagnostic evaluation.¹ If interstitial lung disease is diagnosed, discontinue erlotinib and institute appropriate treatment.¹

Renal Failure

Hepatorenal syndrome or acute renal failure, sometimes fatal, and renal insufficiency, with or without hypokalemia, have been reported.¹ Risk factors include baseline hepatic impairment; severe dehydration caused by diarrhea, vomiting, and/or anorexia; and concurrent chemotherapy.¹

If dehydration occurs, interrupt erlotinib therapy and initiate intensive rehydration measures, particularly in patients at risk for renal failure (e.g., those with preexisting renal disease, medical conditions or drugs that may lead to renal disease, or other predisposing conditions such as advanced age).¹

Periodically monitor renal function and serum electrolytes in patients at risk of dehydration.¹

Hepatic Toxicity

Hepatic failure and hepatorenal syndrome, sometimes fatal, have occurred, particularly in patients with hepatic impairment prior to treatment.¹ (See Hepatic Impairment under Cautions.)

Periodically monitor liver function tests (i.e., serum transaminase, bilirubin, and alkaline phosphatase concentrations).¹ In patients with worsening liver function test results, consider interruption of therapy or dosage reduction with frequent monitoring of liver function tests before changes become severe.¹ If liver function changes are severe (e.g., total bilirubin >3 times ULN and/or serum aminotransferase concentrations >5 times ULN in patients with normal pretreatment values), interrupt or discontinue therapy.¹ If hepatic failure occurs, discontinue therapy.¹

GI Perforation

GI perforation, sometimes fatal, has occurred.^{1 10} Often associated with history of peptic ulcer disease or diverticulitis and concomitant therapy with antiangiogenesis drugs, corticosteroids, NSAIAs, and/or taxane-based chemotherapy.^{1 10} If perforation occurs, permanently discontinue therapy.^{1 10}

Bullous and Exfoliative Skin Disorders

Bullous, blistering, and exfoliative skin reactions, including cases suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis, have occurred; sometimes fatal.^{1 10} If such reactions are severe, interrupt or discontinue therapy.^{1 10}

Myocardial Infarction/Ischemia

Among patients receiving erlotinib and gemcitabine for pancreatic cancer in a randomized trial, 6 patients (2.3%) experienced myocardial infarction/ischemia; one of these patients died.¹

Cerebrovascular Accident

Among patients receiving erlotinib and gemcitabine for pancreatic cancer in a randomized trial, 6 patients (2.3%) experienced cerebrovascular accidents, including one fatal hemorrhagic stroke.¹

Microangiopathic Hemolytic Anemia with Thrombocytopenia

Among patients receiving erlotinib and gemcitabine for pancreatic cancer in a randomized trial, 2 patients (0.8%) developed microangiopathic hemolytic anemia with thrombocytopenia.¹

Corneal Ulceration or Perforation

Corneal ulceration and perforation reported.^{1 10} Abnormal eyelash growth (e.g., ingrowing eyelashes, excessive growth, thickening of eyelashes), keratoconjunctivitis sicca (i.e., dry eye), and keratitis also reported and are potential risk factors for corneal ulceration or perforation.^{1 10} If acute or worsening ocular toxicity (e.g., eye pain) occurs, interrupt or discontinue therapy.^{1 10}

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryolethality demonstrated in animals.¹ Avoid pregnancy during therapy.¹ (See Advice to Patients.) If used during pregnancy, apprise of potential fetal hazard or risk for loss of the pregnancy.¹

Rash

Rash reported frequently.¹ Median time to onset is 8–10 days.¹ Typically is erythematous and maculopapular; may resemble acne with follicular pustules but is histopathologically different.¹ Commonly occurs on the face, upper chest, and back, but may be more generalized or severe (grade 3 or 4) with desquamation.¹ (See Bullous and Exfoliative Skin Disorders under Cautions.)

Based on severity, management may include use of topical corticosteroids or topical anti-infectives with anti-inflammatory properties.¹ (See Advice to Patients.) Dosage reduction or drug discontinuance required in some patients.¹

Diarrhea

Diarrhea frequently reported, including grade 3/4 diarrhea.¹ Median time to onset is 12–15 days.¹

Manage diarrhea with loperamide.¹ If diarrhea becomes severe and is unresponsive to loperamide or results in dehydration, consider reducing erlotinib dosage or temporarily interrupting therapy.¹

Elevated INR and Bleeding

Increased INR and infrequent bleeding (including GI and non-GI bleeding) reported; some of these patients were receiving concomitant warfarin or NSAIA therapy.¹ (See Interactions.)

Therapy Monitoring

Periodically monitor liver function tests (i.e., serum transaminases, bilirubin, and alkaline phosphatase).¹

Periodically monitor renal function and serum electrolytes in patients at risk of dehydration.¹

Specific Populations

Pregnancy

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

Lactation

Not known whether distributed into milk.¹ Discontinue nursing or the drug because of potential risk to nursing infants.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 2}

Geriatric Use

In clinical trial of erlotinib monotherapy for non-small cell lung cancer, no overall differences in safety and efficacy relative to younger adults.¹

In clinical trial for pancreatic cancer, survival benefit for erlotinib/gemcitabine versus placebo/gemcitabine was less clear in geriatric patients; no meaningful differences in safety or pharmacokinetics relative to younger adults.¹

Hepatic Impairment

Use with caution since erlotinib undergoes hepatic metabolism and biliary excretion;¹ extreme caution advised in patients with severe hepatic impairment (total bilirubin >3 times ULN).^{1 8} Close monitoring required in patients with total bilirubin exceeding ULN or Child-Pugh class A, B, or C.^{1 8} (See Special Populations under Pharmacokinetics.)

If worsening of liver dysfunction occurs, consider interruption of therapy or dosage reduction accompanied by frequent monitoring of liver function tests before changes in liver function become severe.¹ If severe changes in liver function test results (e.g., doubling of bilirubin, tripling of serum aminotransferase concentrations) occur in patients with hepatic dysfunction prior to treatment, interrupt or discontinue therapy.^{1 8}

Renal Impairment

Safety and efficacy not established.¹

Common Adverse Effects

Erlotinib monotherapy for non-small cell lung cancer: Rash,¹ diarrhea,¹ anorexia,¹ fatigue,¹ dyspnea,¹ cough,¹ nausea,¹ infection,¹ vomiting,¹ stomatitis,¹ pruritus,¹ dry skin,¹ conjunctivitis,¹ keratoconjunctivitis sicca,¹ abdominal pain.¹

Erlotinib and gemcitabine for pancreatic cancer: Fatigue,¹ rash,¹ nausea,¹ anorexia,¹ diarrhea,¹ abdominal pain,¹ vomiting,¹ decreased weight,¹ infection,¹ edema,¹ pyrexia,¹ constipation.¹

Interactions for Erlotinib

Extensively metabolized by CYP isoenzymes, principally CYP3A4 and, to a lesser extent, CYP1A1 and CYP1A2.¹

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma erlotinib concentrations).¹ Caution when used concomitantly with potent CYP3A4 inhibitors.¹ Consider reducing erlotinib dosage if severe adverse effects occur.¹ (See Specific Drugs and Foods under Interactions.)

Inhibitors of CYP3A4 and CYP1A2: Potential pharmacokinetic interaction (increased plasma erlotinib concentrations).¹ Consider reducing erlotinib dosage if severe adverse effects occur.¹ (See Specific Drugs and Foods under Interactions.)

Inducers of CYP3A4: Potential pharmacokinetic interaction (increased erlotinib clearance, resulting in decreased plasma erlotinib concentrations).¹ Avoid concomitant use.¹ If concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if the CYP3A4 inducer is discontinued, immediately reduce erlotinib dosage to the recommended starting dosage.¹ (See Specific Drugs and Foods under Interactions.)

Drugs Affecting Gastric Acidity

Pharmacokinetic interaction (decreased solubility and reduced oral bioavailability of erlotinib) with drugs that increase pH of upper GI tract (e.g., proton-pump inhibitors, histamine H₂-receptor antagonists).¹ (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Antacids	Effect of antacids on erlotinib disposition not established1	Although effects on erlotinib not established, antacids may be considered as an alternative to histamine H2-receptor antagonists or proton-pump inhibitors; if use is necessary, separate antacid dose and erlotinib dose by several hours1
Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole)	Possible increased plasma erlotinib concentrations; ketoconazole increased erlotinib AUC1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Antimycobacterials, rifamycins (e.g., rifabutin, rifampin, rifapentine)	Possible decreased plasma erlotinib concentrations1 Rifampin increased erlotinib clearance, resulting in decreased plasma erlotinib concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if the rifamycin is discontinued, immediately reduce erlotinib dosage to recommended starting dosage1 Maximum erlotinib dose studied in combination with rifampin: 450 mg1
Carbamazepine	Possible decreased plasma erlotinib concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if carbamazepine is discontinued, immediately reduce erlotinib dosage to recommended starting dosage1
Cigarette smoking	Decreased systemic exposure to erlotinib1	Advise patients to stop smoking1 If patient continues to smoke, consider increasing erlotinib dose (maximum 300 mg) with close monitoring; efficacy and safety of dosages exceeding the recommended starting dosage not established in smokers beyond 14 days1 Upon cessation of smoking, immediately reduce erlotinib dosage to recommended starting dosage1
Ciprofloxacin	Increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Clarithromycin	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Gemcitabine	Pharmacokinetic interaction unlikely1
Grapefruit or grapefruit juice	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Histamine H2-receptor antagonists	Decreased solubility and oral bioavailability of erlotinib1	Antacids may be considered as an alternative, but effect on erlotinib disposition not studied1 (see antacids entry in table)
HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Midazolam	Decreased systemic exposure to midazolam1
Nefazodone	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Phenobarbital	Possible decreased plasma erlotinib concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if phenobarbital is discontinued, immediately reduce erlotinib dosage to recommended starting dosage1
Phenytoin	Possible decreased plasma erlotinib concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if phenytoin is discontinued, immediately reduce erlotinib dosage to recommended starting dosage1
Proton-pump inhibitors	Decreased solubility and oral bioavailability of erlotinib1	If possible, avoid concomitant use1 Increasing erlotinib dosage is not likely to compensate for the decrease in systemic exposure; separation of doses may not eliminate the interaction because of prolonged effect of proton-pump inhibitors on gastric pH1 Antacids may be considered as an alternative, but effect on erlotinib disposition not studied1 (see antacids entry in table)
St. John’s wort (Hypericum perforatum)	Possible decreased plasma erlotinib concentrations1	Avoid concomitant use; if concomitant use cannot be avoided, consider increasing erlotinib dosage as tolerated at 2-week intervals with close monitoring; if St. John's wort is discontinued, immediately reduce erlotinib dosage to recommended starting dosage1
Telithromycin	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Troleandomycin	Possible increased plasma erlotinib concentrations1	Use concomitantly with caution; consider reducing erlotinib dosage if severe adverse effects occur1
Warfarin or other coumarin-derivative anticoagulants	Increased INR and possible bleeding (including GI and non-GI bleeding)1 2	Monitor PT or INR regularly1

Erlotinib Pharmacokinetics

Absorption

Bioavailability

Approximately 60% absorbed from the GI tract.¹

Peak plasma concentrations occur at 4 hours following oral administration.¹

Food

Presence of food in the GI tract increases oral bioavailability to almost 100%.¹

Distribution

Plasma Protein Binding

Approximately 93% (mainly to albumin and α₁-acid glycoprotein).¹

Elimination

Metabolism

Extensively metabolized by CYP isoenzymes, principally CYP3A4 and, to a lesser extent, CYP1A1 and CYP1A2.¹

Elimination Route

Excreted mainly as metabolites in feces (83%) via biliary excretion and in urine (8%).¹

Half-life

Approximately 36 hours.¹

Special Populations

Clearance rate is approximately 24% higher in smokers.¹

Although erlotinib is eliminated mainly by the liver, systemic exposure was not substantially altered in patients with Child-Pugh class B hepatic impairment relative to those with adequate hepatic function (including individuals with primary liver cancer or hepatic metastases).¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

ActionsActions

• 
  

  Antineoplastic agent; a kinase inhibitor.¹

  
  


• 
  

  Exact mechanism of antineoplastic activity not fully elucidated.¹ Appears to inhibit intracellular phosphorylation of tyrosine kinase associated with epidermal growth factor receptor (EGFR), which is expressed on the surface of normal and cancer cells.¹ Specificity with regard to other tyrosine kinase receptors not fully characterized.¹

  
  

Advice to Patients

• 
  

  Risk of adverse pulmonary, dermatologic, GI, or ocular effects.¹ Importance of seeking medical advice promptly if the following manifestations occur: new onset or exacerbation of unexplained shortness of breath or cough; onset or exacerbation of rash; severe or persistent diarrhea, nausea, anorexia, or vomiting; or ocular pain or irritation.¹

  
  


• 
  

  Importance of skin care (e.g., alcohol-free emollient cream, use of sunscreen or avoidance of sun exposure), to minimize the risk of skin reactions; avoidance of acne preparations with drying properties, which may aggravate dry skin and erythema.¹

  
  


• 
  

  Advise smokers to stop smoking; smoking may reduce efficacy of erlotinib.¹ (See Specific Drugs and Foods under Interactions.)

  
  


• 
  

  Importance of women using an effective method of contraception during and for at least 2 weeks after discontinuance of therapy.¹ If pregnancy occurs, advise patient of risk to the fetus.¹

  
  


• 
  

  Importance of women informing clinicians if they plan to breast-feed.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. (See Cautions.)

  
  

Preparations

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

Erlotinib Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	25 mg (of erlotinib)	Tarceva	Genentech
		100 mg (of erlotinib)	Tarceva	Genentech
		150 mg (of erlotinib)	Tarceva	Genentech

Comparative Pricing

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

Tarceva 100MG Tablets (GENENTECH): 30/$4153.17 or 90/$12258.63

Tarceva 150MG Tablets (GENENTECH): 30/$4721.64 or 90/$13865.33

Tarceva 25MG Tablets (GENENTECH): 30/$1523.87 or 90/$4454.7

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 October 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

1. Genentech. Tarceva (erlotinib) tablets prescribing information. South San Francisco, CA; 2009 Apr.

2. Genentech, South San Francisco, CA: Personal communication.

3. Shepherd FA, Pereira J, Ciuleanu TE et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005; 353: 123-32.

4. Herbst RS, Prager D, Hermann R et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005; 23:5892-9. [PubMed 16043829]

5. Gatzemeier U, Pluzanska A, Szczesna A et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007; 25:1545-52. [PubMed 17442998]

6. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007; 25:1960-6. [PubMed 17452677]

7. Makris D, Scherpereel A, Copin MC et al. Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer. BMC Cancer. 2007; 7:150. [PubMed 17683587]

8. Witt K, Barron H. Dear healthcare provider letter: important safety information regarding the use of Tarceva (erlotinib) in patients with hepatic impairment and other safety-related updates. South San Francisco, CA: Genentech/Melville, NY: OSI Pharmaceuticals; 2008 Sep.

10. Witt K, Barron H. Dear healthcare provider letter: important safety information regarding GI perforations, serious skin toxicity, and ocular disorders with the use of Tarceva (erlotinib). South San Franciso, CA: Genentech/Melville, NY: OSI Pharmaceuticals; 2009 Apr.

More Erlotinib resources

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

• Erlotinib MedFacts Consumer Leaflet (Wolters Kluwer)


• Erlotinib Professional Patient Advice (Wolters Kluwer)


• erlotinib Advanced Consumer (Micromedex) - Includes Dosage Information


• Tarceva Prescribing Information (FDA)


• Tarceva Consumer Overview

Compare Erlotinib with other medications

• Non-Small Cell Lung Cancer
• Pancreatic Cancer
• Renal Cell Carcinoma

Coartem

artemether and lumefantrine

Dosage Form: tablet
FULL PRESCRIBING INFORMATION

Indications and Usage for Coartem

Coartem (artemether/lumefantrine) Tablets are indicated for treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum in patients of 5 kg bodyweight and above. Coartem Tablets have been shown to be effective in geographical regions where resistance to chloroquine has been reported [see Clinical Studies (14.1)].

Limitations of Use:

• Coartem Tablets are not approved for patients with severe or complicated P. falciparum malaria.
  


• Coartem Tablets are not approved for the prevention of malaria.

Coartem Dosage and Administration

Administration Instructions

Coartem Tablets should be taken with food. Patients with acute malaria are frequently averse to food. Patients should be encouraged to resume normal eating as soon as food can be tolerated since this improves absorption of artemether and lumefantrine.

For patients who are unable to swallow the tablets such as infants and children, Coartem Tablets may be crushed and mixed with a small amount of water (one to two teaspoons) in a clean container for administration immediately prior to use. The container can be rinsed with more water and the contents swallowed by the patient. The crushed tablet preparation should be followed whenever possible by food/drink (e.g., milk, formula, pudding, broth, and porridge).

In the event of vomiting within 1 to 2 hours of administration, a repeat dose should be taken. If the repeat dose is vomited, the patient should be given an alternative antimalarial for treatment.

Dosage in Adult Patients (>16 years of age)

A 3-day treatment schedule with a total of 6 doses is recommended for adult patients with a bodyweight of 35 kg and above:

Four tablets as a single initial dose, 4 tablets again after 8 hours and then 4 tablets twice daily (morning and evening) for the following two days (total course of 24 tablets).

For patients weighing less than 35 kg, see Dosage in Pediatric Patients (2.3).

Dosage in Pediatric Patients

A 3-day treatment schedule with a total of 6 doses is recommended as below:

5 kg to less than 15 kg bodyweight: One tablet as an initial dose, 1 tablet again after 8 hours and then 1 tablet twice daily (morning and evening) for the following two days (total course of 6 tablets).

15 kg to less than 25 kg bodyweight: Two tablets as an initial dose, 2 tablets again after 8 hours and then 2 tablets twice daily (morning and evening) for the following two days (total course of 12 tablets).

25 kg to less than 35 kg bodyweight: Three tablets as an initial dose, 3 tablets again after 8 hours and then 3 tablets twice daily (morning and evening) for the following two days (total course of 18 tablets).

35 kg bodyweight and above: Four tablets as a single initial dose, 4 tablets again after 8 hours and then 4 tablets twice daily (morning and evening) for the following two days (total course of 24 tablets).

Dosage in Patients with Hepatic or Renal Impairment

No specific pharmacokinetic studies have been carried out in patients with hepatic or renal impairment. Most patients with acute malaria present with some degree of related hepatic and/or renal impairment. In clinical studies, the adverse event profile did not differ in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function. No specific dose adjustments are needed for patients with mild or moderate hepatic impairment.

In clinical studies, the adverse event profile did not differ in patients with mild or moderate renal impairment compared to patients with normal renal function. There were few patients with severe renal impairment in clinical studies. There is no significant renal excretion of lumefantrine, artemether and dihydroartemisinin (DHA) in healthy volunteers and while clinical experience in this population is limited, no dose adjustment is recommended.

Caution should be exercised when administering Coartem Tablets in patients with severe hepatic or renal impairment [see Warnings and Precautions (5.6)].

Dosage Forms and Strengths

Coartem Tablets contain 20 mg of artemether and 120 mg of lumefantrine. Coartem Tablets are supplied as yellow, round, flat tablets with beveled edges and scored on one side. Tablets are imprinted with N/C on one side and CG on the other side.

Contraindications

Hypersensitivity

• Patients hypersensitive to artemether, lumefantrine, or to any of the excipients of Coartem Tablets [see Adverse Reactions (6.3)].

Warnings and Precautions

Prolongation of the QT Interval

Some antimalarials (e.g., halofantrine, quinine, quinidine) including Coartem Tablets have been associated with prolongation of the QT interval on the electrocardiogram.

Coartem Tablets should be avoided in patients:

• with congenital prolongation of the QT interval (e.g., long QT syndrome) or any other clinical condition known to prolong the QTc interval such as patients with a history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
  


• with a family history of congenital prolongation of the QT interval or sudden death.
  


• with known disturbances of electrolyte balance, e.g., hypokalemia or hypomagnesemia.
  


• receiving other medications that prolong the QT interval, such as class IA (quinidine, procainamide, disopyramide), or class III (amiodarone, sotalol) antiarrhythmic agents; antipsychotics (pimozide, ziprasidone); antidepressants; certain antibiotics (macrolide antibiotics, fluoroquinolone antibiotics, imidazole, and triazole antifungal agents); certain non-sedating antihistaminics (terfenadine, astemizole), or cisapride [see Clinical Pharmacology (12.5)].
  


• receiving medications that are metabolized by the cytochrome enzyme CYP2D6 which also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.4), Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

Use of QT Prolonging Drugs and Other Antimalarials 

Halofantrine and Coartem Tablets should not be administered within one month of each other due to the long elimination half-life of lumefantrine (3-6 days) and potential additive effects on the QT interval [see Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

Antimalarials should not be given concomitantly with Coartem Tablets, unless there is no other treatment option, due to limited safety data.

Drugs that prolong the QT interval, including antimalarials such as quinine and quinidine, should be used cautiously following Coartem Tablets, due to the long elimination half-life of lumefantrine (3-6 days) and the potential for additive effects on the QT interval.

[see Warnings and Precautions (5.1), Drug Interactions (7.5), and Clinical Pharmacology (12.3)].

If mefloquine is administered immediately prior to Coartem Tablets there may be a decreased exposure to lumefantrine, possibly due to a mefloquine-induced decrease in bile production. Therefore, patients should be monitored for decreased efficacy and food consumption should be encouraged while taking Coartem Tablets [see Dosage and Administration (2.1), Drug Interactions (7.2), and Clinical Pharmacology (12.3)].

Drug Interactions with CYP3A4 

When Coartem Tablets are co-administered with substrates of CYP3A4 it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. When Coartem Tablets are co-administered with an inhibitor of CYP3A4, including grapefruit juice it may result in increased concentrations of artemether and/or lumefantrine and potentiate QT prolongation. When Coartem Tablets are co-administered with inducers of CYP3A4 it may result in decreased concentrations of artemether and/or lumefantrine and loss of anti-malarial efficacy [see Drug Interactions (7.1)].

Drugs that have a mixed effect on CYP3A4, especially Anti-Retroviral drugs, and those that have an effect on the QT interval should be used with caution in patients taking Coartem Tablets [see Drug Interactions (7.3)].

Coartem Tablets may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control [see Drug Interactions (7.3)].

Drug Interactions with CYP2D6

Administration of Coartem Tablets with drugs that are metabolized by CYP2D6 may significantly increase plasma concentrations of the co-administered drug and increase the risk of adverse effects. Many of the drugs metabolized by CYP2D6 can prolong the QT interval and should not be administered with Coartem Tablets due to the potential additive effect on the QT interval (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.1), Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

Recrudescence

Food enhances absorption of artemether and lumefantrine following administration of Coartem Tablets. Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater [see Dosage and Administration (2.1)].

In the event of recrudescent P. falciparum infection after treatment with Coartem Tablets, patients should be treated with a different antimalarial drug.

Hepatic and Renal Impairment

Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment [see Dosage and Administration (2.4)].

Plasmodium vivax Infection

Coartem Tablets have been shown in limited data (43 patients) to be effective in treating the erythrocytic stage of P. vivax infection. However, relapsing malaria caused by P. vivax requires additional treatment with other antimalarial agents to achieve radical cure i.e., eradicate any hypnozoites forms that may remain dormant in the liver.

Adverse Reactions

Serious Adverse Reactions

The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:

• Hypersensitivity Reactions [see Contraindications (4.1) and Postmarketing Experience (6.3)].

Clinical Studies Experience

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

The data described below reflect exposure to a 6-dose regimen of Coartem Tablets in 1,979 patients including 647 adults (older than 16 years) and 1,332 children (16 years and younger). For the 6-dose regimen, Coartem Tablets was studied in active-controlled (366 patients) and non-controlled, open-label trials (1,613 patients). The 6-dose Coartem Tablets population was patients with malaria between ages 2 months and 71 years: 67% (1,332) were 16 years and younger and 33% (647) were older than 16 years. Males represented 73% and 53% of the adult and pediatric populations, respectively. The majority of adult patients were enrolled in studies in Thailand, while the majority of pediatric patients were enrolled in Africa.

Tables 1 and 2 show the most frequently reported adverse reactions (≥3%) in adults and children respectively who received the 6-dose regimen of Coartem Tablets. Adverse reactions collected in clinical trials included signs and symptoms at baseline but only treatment emergent adverse events, defined as events that appeared or worsened after the start of treatment, are presented below. In adults, the most frequently reported adverse reactions were headache, anorexia, dizziness, and asthenia. In children, the adverse reactions were pyrexia, cough, vomiting, anorexia, and headache. Most adverse reactions were mild, did not lead to discontinuation of study medication, and resolved.

In limited comparative studies, the adverse reaction profile of Coartem Tablets appeared similar to that of another antimalarial regimen.

Discontinuation of Coartem Tablets due to adverse drug reactions occurred in 1.1% of patients treated with the 6-dose regimen overall: 0.2% (1/647) in adults and 1.6% (21/1,332) in children.

Table 1: Adverse Reactions Occurring in 3% or More of Adult Patients Treated in Clinical Trials with the 6-dose Regimen of Coartem Tablets

System Organ Class	Preferred Term	Adults* N=647 (%)
Nervous system disorders	Headache	360 (56)
	Dizziness	253 (39)
Metabolism and nutrition disorders	Anorexia	260 (40)
General disorders and administration site conditions	Asthenia	243 (38)
	Pyrexia	159 (25)
	Chills	147 (23)
	Fatigue	111 (17)
	Malaise	20 (3)
Musculoskeletal and connective tissue disorders	Arthralgia	219 (34)
	Myalgia	206 (32)
Gastrointestinal disorders	Nausea	169 (26)
	Vomiting	113 (17)
	Abdominal pain	112 (17)
	Diarrhea	46 (7)
Psychiatric disorders	Sleep disorder	144 (22)
	Insomnia	32 (5)
Cardiac disorders	Palpitations	115 (18)
Hepatobiliary disorders	Hepatomegaly	59 (9)
Blood and lymphatic system disorders	Splenomegaly	57 (9)
	Anemia	23 (4)
Respiratory, thoracic and mediastinal disorders	Cough	37 (6)
Skin and subcutaneous tissue disorders	Pruritus	24 (4)
	Rash	21 (3)
Ear and labyrinth disorders	Vertigo	21 (3)
Infections and infestations	Malaria	18 (3)
	Nasopharyngitis	17 (3)

* Adult patients defined as >16 years of age

Table 2: Adverse Reactions Occurring in 3% or More of Pediatric Patients Treated in Clinical Trials with the 6-dose Regimen of Coartem Tablets

System Organ Class	Preferred Term	Children* N=1,332 (%)
General disorders and administration site conditions	Pyrexia	381 (29)
	Chills	72 (5)
	Asthenia	63 (5)
	Fatigue	46 (3)
Respiratory, thoracic and mediastinal disorders	Cough	302 (23)
Gastrointestinal disorders	Vomiting	242 (18)
	Abdominal pain	112 (8)
	Diarrhea	100 (8)
	Nausea	61 (5)
Infections and infestations	Plasmodium falciparum infection	224 (17)
	Rhinitis	51 (4)
Metabolism and nutrition disorders	Anorexia	175 (13)
Nervous system disorders	Headache	168 (13)
	Dizziness	56 (4)
Blood and lymphatic system disorders	Splenomegaly	124 (9)
	Anemia	115 (9)
Hepatobiliary disorders	Hepatomegaly	75 (6)
Investigations	Aspartate aminotransferase increased	51 (4)
Musculoskeletal and connective tissue disorders	Arthralgia	39 (3)
	Myalgia	39 (3)
Skin and subcutaneous tissue disorders	Rash	38 (3)

* Children defined as patients ≤16 years of age

Clinically significant adverse reactions reported in adults and/or children treated with the 6-dose regimen of Coartem Tablets which occurred in clinical studies at <3% regardless of causality are listed below:

      Blood and lymphatic system disorders: eosinophilia

      Ear and labyrinth disorders: tinnitus

      Eye disorders: conjunctivitis

      Gastrointestinal disorders: constipation, dyspepsia, dysphagia, peptic ulcer

      General disorders: gait disturbance

      Infections and infestations: abscess, acrodermatitis, bronchitis, ear infection, gastroenteritis, helminthic

      infection, hookworm infection, impetigo, influenza, lower respiratory tract infection, malaria,

      nasopharyngitis, oral herpes, pneumonia, respiratory tract infection, subcutaneous abscess, upper

      respiratory tract infection, urinary tract infection

      Investigations: alanine aminotransferase increased, aspartate aminotransferase increased hematocrit

      decreased, lymphocyte morphology abnormal, platelet count decreased, platelet count increased, white

      blood cell count decreased, white blood cell count increased

      Metabolism and nutrition disorders: hypokalemia

      Musculoskeletal and connective tissue disorders: back pain

      Nervous system disorders: ataxia, clonus, fine motor delay, hyperreflexia, hypoaesthesia, nystagmus,

      tremor

      Psychiatric disorders: agitation, mood swings

      Renal and urinary disorders: hematuria, proteinuria

      Respiratory, thoracic and mediastinal disorders: asthma, pharyngo-laryngeal pain

      Skin and subcutaneous tissue disorders: urticaria

Postmarketing Experience

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

• Hypersensitivity including urticaria and angioedema. Serious skin reactions (bullous eruption) have been rarely reported.

Drug Interactions

Ketoconazole 

Concurrent oral administration of ketoconazole, a potent CYP3A4 inhibitor, with a single dose of Coartem Tablets resulted in a moderate increase in exposure to artemether, dihydroartemisinin (DHA, metabolite of artemether), and lumefantrine in a study of 15 healthy subjects. No dose adjustment of Coartem Tablets is necessary when administered with ketoconazole or other potent CYP3A4 inhibitors. However, due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, Coartem Tablets should be used cautiously with drugs that inhibit CYP3A4 [see Warnings and Precautions (5.1, 5.3)].

Prior Use of Mefloquine 

Administration of three doses of mefloquine followed 12 hours later by a 6-dose regimen of Coartem Tablets in 14 healthy volunteers demonstrated no effect of mefloquine on plasma concentrations of artemether or the artemether/DHA ratio. However, exposure to lumefantrine was reduced, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production. Patients should be monitored for decreased efficacy and food consumption should be encouraged with administration of Coartem Tablets [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

CYP3A4 Metabolism: Hormonal Contraceptives and Anti-Retroviral Drugs 

Artemether induces CYP3A4 and both artemether and lumefantrine are metabolized primarily by CYP3A4.

Coartem Tablets may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

Anti-Retroviral drugs (ARTs), such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, are known to have variable patterns of inhibition, induction or competition for CYP3A4. No formal drug-drug interaction studies between Coartem Tablets and ARTs have been performed. However, Coartem Tablets should be used cautiously in patients on ARTs as the result may be an increase in lumefantrine concentrations causing QT prolongation or a decrease in concentrations of the ART resulting in loss of efficacy, or a decrease in artemether and/or lumefantrine concentrations resulting in loss of antimalarial efficacy of Coartem Tablets [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

CYP2D6 Substrates

Lumefantrine inhibits CYP2D6 in vitro. Administration of Coartem Tablets with drugs that are metabolized by CYP2D6 may significantly increase plasma concentrations of the co-administered drug and increase the risk of adverse effects. Many of the drugs metabolized by CYP2D6 can prolong the QT interval and should not be administered with Coartem Tablets due to the potential additive effect on the QT interval (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.1, 5.4) and Clinical Pharmacology (12.3)].

Sequential Use of Quinine

A single dose of intravenous quinine (10 mg/kg bodyweight) concurrent with the final dose of a 6-dose regimen of Coartem Tablets demonstrated no effect of intravenous quinine on the systemic exposure of DHA or lumefantrine. Quinine exposure was also not altered. Exposure to artemether was decreased. This decrease in artemether exposure is not thought to be clinically significant. However, quinine and other drugs that prolong the QT interval should be used cautiously following treatment with Coartem Tablets due to the long elimination half life of lumefantrine and the potential for additive QT effects. [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to Coartem Tablets (including a third of patients who were exposed in the first trimester), and published data of over 1,000 pregnant patients who were exposed to artemisinin derivatives, did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rate.

The efficacy of Coartem Tablets in the treatment of acute, uncomplicated malaria in pregnant women has not been established.

Coartem Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant rats dosed during the period of organogenesis at or higher than a dose of about half the highest clinical dose of 1120 mg artemether-lumefantrine per day (based on body surface area comparisons), showed increases in fetal loss, early resorptions and post implantation loss. No adverse effects were observed in animals dosed at about one-third the highest clinical dose. Similarly, dosing in pregnant rabbits at about three times the clinical dose (based on body surface area comparisons) resulted in abortions, preimplantation loss, post implantation loss and decreases in the number of live fetuses. No adverse reproductive effects were detected in rabbits at two times the clinical dose. Embryo-fetal loss is a significant reproductive toxicity. Other artemisinins are known to be embryotoxic in animals. However, because metabolic profiles in animals and humans are dissimilar, artemether exposures in animals may not be predictive of human exposures [see Nonclinical Toxicology (13.2)]. These data cannot rule out an increased risk for early pregnancy loss or fetal defects in humans.

Nursing Mothers

It is not known whether artemether or lumefantrine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Coartem Tablets are administered to a nursing woman. Animal data suggest both artemether and lumefantrine are excreted into breast milk. The benefits of breastfeeding to mother and infant should be weighed against potential risk from infant exposure to artemether and lumefantrine through breast milk.

Pediatric Use

The safety and effectiveness of Coartem Tablets have been established for the treatment of acute, uncomplicated malaria in studies involving pediatric patients weighing 5 kg or more [see Clinical Studies (14.1)]. The safety and efficacy have not been established in pediatric patients who weigh less than 5 kg. Children from non-endemic countries were not included in clinical trials.

Geriatric Use

Clinical studies of Coartem Tablets did not include sufficient numbers of subjects aged 65 years and over to determine they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Coartem Tablets.

Hepatic and Renal Impairment

No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether and DHA, no dose adjustment for the use of Coartem in patients with renal impairment is advised. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. [see Dosage and Administration (2.4) and Warnings and Precautions (5.6)].

Overdosage

There is no information on overdoses of Coartem Tablets higher than the doses recommended for treatment.

In cases of suspected overdosage, symptomatic and supportive therapy, which would include ECG and blood electrolyte monitoring, should be given as appropriate.

Coartem Description

Coartem Tablets contain a fixed combination of two antimalarial active ingredients, artemether, an artemisinin derivative, and lumefantrine. Both components are blood schizontocides. The chemical name of artemether is (3R,5aS,6R,8aS,9R,10S,12R,12aR) - decahydro - 10 - methoxy - 3,6,9 - trimethyl - 3,12 - epoxy - 12H - pyrano[4,3 - j] - 1,2 - benzodioxepine. Artemether is a white, crystalline powder that is freely soluble in acetone, soluble in methanol and ethanol, and practically insoluble in water. It has the empirical formula C16H26O5 with a molecular weight of 298.4, and the following structural formula:

The chemical name of lumefantrine is (±)-2-dibutylamino-1-[2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluorene-4-yl]ethanol. Lumefantrine is a yellow, crystalline powder that is freely soluble in N,N-dimethylformamide, chloroform, and ethyl acetate; soluble in dichloromethane; slightly soluble in ethanol and methanol; and insoluble in water. It has the empirical formula C30H32Cl3NO with a molecular weight of 528.9, and the following structural formula:

     

Coartem Tablets are for oral administration. Each Coartem Tablet contains 20 mg of artemether and 120 mg lumefantrine. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, and polysorbate 80.

Coartem - Clinical Pharmacology

Mechanism of Action

Coartem Tablets, a fixed dose combination of artemether and lumefantrine in the ratio of 1:6, is an antimalarial agent [see Clinical Pharmacology (12.4)].

Pharmacokinetics

Absorption

Following administration of Coartem Tablets to healthy volunteers and patients with malaria, artemether is absorbed with peak plasma concentrations reached about 2 hours after dosing. Absorption of lumefantrine, a highly lipophilic compound, starts after a lag-time of up to 2 hours, with peak plasma concentrations about 6 to 8 hours after administration. The single dose (4 tablets) pharmacokinetic parameters for artemether, dihydroartemisinin (DHA), an active antimalarial metabolite of artemether, and lumefantrine in adult Caucasian healthy volunteers are given in Table 3. Multiple dose data after the 6-dose regimen of Coartem Tablets in adult malaria patients are given in Table 4.

Table 3: Single Dose Pharmacokinetic Parametersa for Artemether, Dihydroartemisinin (DHA), and Lumefantrine under Fed Conditions

	Study 2102 (n=50)	Study 2104 (n=48)
Artemether
Cmax (ng/mL)	60.0 ± 32.5	83.8 ± 59.7
tmax (h)	1.50	2.00
AUClast (ng·h/mL)	146 ± 72.2	259 ± 150
t½ (h)	1.6 ± 0.7	2.2 ± 1.9
DHA
Cmax (ng/mL)	104 ± 35.3	90.4 ± 48.9
tmax (h)	1.76	2.00
AUClast (ng·h/mL)	284 ± 83.8	285 ± 98.0
t½ (h)	1.6 ± 0.6	2.2 ± 1.5
Lumefantrine
Cmax (µg/mL)	7.38 ± 3.19	9.80 ± 4.20
tmax (h)	6.01	8.00
AUClast (µg·h/mL)	158 ± 70.1	243 ± 117
t½ (h)	101 ± 35.6	119 ± 51.0

aMean ± SD Cmax, AUClast, t½ and Median tmax

Food enhances the absorption of both artemether and lumefantrine. In healthy volunteers, the relative bioavailability of artemether was increased between two- to three-fold, and that of lumefantrine sixteen-fold when Coartem Tablets were taken after a high-fat meal compared under fasted conditions. . Patients should be encouraged to take Coartem Tablets with a meal as soon as food can be tolerated [see Dosage and Administration (2.1)].

Distribution

Artemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin is also bound to human serum proteins (47% to 76%). Protein binding to human plasma proteins is linear.

Biotransformation

In human liver microsomes and recombinant CYP450 enzymes, the metabolism of artemether was catalyzed predominantly by CYP3A4/5. Dihydroartemisinin (DHA) is an active metabolite of artemether. The metabolism of artemether was also catalyzed to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. In vitro studies with artemether at therapeutic concentrations revealed no significant inhibition of the metabolic activities of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11.

During repeated administration of Coartem Tablets, systemic exposure of artemether decreased significantly, while concentrations of DHA increased, although not to a statistically significant degree. The artemether/DHA AUC ratio is 1.2 after a single dose and 0.3 after 6 doses given over 3 days. This suggests that there was induction of CYP3A4/5 responsible for the metabolism of artemether.

In human liver microsomes and in recombinant CYP450 enzymes, lumefantrine was metabolized mainly by CYP3A4 to desbutyl-lumefantrine. The systemic exposure to the metabolite desbutyl-lumefantrine was less than 1% of the exposure to the parent compound. In vitro, lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations.

Caution is recommended when combining Coartem Tablets with substrates, inhibitors, or inducers of CYP3A4, especially anti-retroviral drugs and those that prolong the QT interval (e.g., macrolide antibiotics, pimozide, terfenadine, astemizole, cisapride) [see Warnings and Precautions (5.1, 5.3)].

Co-administration of Coartem Tablets with CYP2D6 substrates may result in increased plasma concentrations of the CYP2D6 substrate and increase the risk of adverse reactions. In addition, many of the drugs metabolized by CYP2D6 can prolong the QT interval and should not be administered with Coartem Tablets due to the potential additive effect on the QT interval (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.1, 5.4)].

Elimination

Artemether and DHA are cleared from plasma with an elimination half-life of about 2 hours. Lumefantrine is eliminated more slowly, with a terminal half-life of 3-6 days in healthy volunteers and in patients with falciparum malaria. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of artemether and lumefantrine.

In 16 healthy volunteers, neither lumefantrine nor artemether was found in the urine after administration of Coartem, and urinary excretion of DHA amounted to less than 0.01% of the artemether dose.

Hepatic and Renal Impairment

No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. There is no significant renal excretion of lumefantrine, artemether and DHA in healthy volunteers and while clinical experience in this population is limited, no dose adjustment in renal impairment is recommended [see Dosage and Administration (2.4)].

Pediatric Patients

The PK of artemether, DHA, and lumefantrine were obtained in two pediatric studies by sparse sampling using a population based approach. PK estimates derived from a composite plasma concentration profile for artemether, DHA, and lumefantrine are provided in Table 4.

Systemic exposure to artemether, DHA, and lumefantrine, when dosed on a mg/kg body weight basis in pediatric patients (≥5 to <35 kg body weight), is comparable to that of the recommended dosing regimen in adult patients.

Table 4: Summary of Pharmacokinetic Parameters for Lumefantrine, Artemether and DHA in Pediatric and Adult Patients with Malaria Following Administration of a 6-dose Regimen of Coartem Tablets

	Pediatric patients (body weight, kg)2
Drug	Adults1	5 - <15			15 - <25		25 - <35
Lumefantrine
Mean Cmax, range (μg/mL)	5.60 - 9.0		4.71 – 12.6			Not Available
Mean AUClast, range (μg·h/mL)	410 - 561		372 – 699			Not Available
Artemether
Mean Cmax ± SD (ng/mL)	186 ± 125	223 ± 309		198 ± 179			174 ± 145
Dihydroartemisinin
Mean Cmax ± SD (ng/mL)	101 ± 58	54.7 ± 58.9		79.8 ± 80.5			65.3 ± 23.6
1 There are a total of 181 adults for lumefantrine pharmacokinetic parameters and a total of 25 adults for artemether and dihydroartemisin pharmacokinetic parameters. 2There are 477 children for the lumefantrine pharmacokinetic parameters; for artemether and dihydroartemisinin pharmacokinetic parameters there are 55, 29, and 8 children for the 5 to <15, 15 to <25 and the 25 to <35 kg groups, respectively.

Geriatric Patients

No specific pharmacokinetic studies have been performed in patients older than 65 years of age.

Drug Interactions

Ketoconazole (potent CYP3A4 inhibitor) 

Concurrent oral administration of ketoconazole (400 mg on Day 1 followed by 200 mg on days 2, 3, 4 and 5) with Coartem Tablets (single dose of 4 tablets of 20 mg artemether/120 mg lumefantrine per tablet) with a meal led to an increase in exposure, in terms of area under the curve (AUC), of artemether (2.3-fold), DHA (1.5 fold), and lumefantrine (1.6-fold) in 13 healthy subjects. The pharmacokinetics of ketoconazole were not evaluated. Based on this study, dose adjustment of Coartem Tablets is considered unnecessary when administered with ketoconazole or other CYP3A4 inhibitors. However, due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, Coartem Tablets should be used cautiously with other drugs that inhibit CYP3A4 (e.g., anti-retroviral drugs, macrolide antibiotics, antidepressants, imidazole antifungal agents) [see Warnings and Precautions (5.1, 5.3)].

Antimalarials

The oral administration of mefloquine in 14 healthy volunteers administered as three doses of 500 mg, 250 mg and 250 mg, followed 12 hours later by Coartem Tablets (6 doses of 4 tablets of 20 mg artemether/120 mg lumefantrine per tablet), had no effect on plasma concentrations of artemether or the artemether/DHA ratio. In the same study, there was a 30% reduction in Cmax and 40% reduction in AUC of lumefantrine, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production.

Intravenous administration of a single dose of quinine (10 mg/kg bodyweight) concurrent with the last dose of a 6-dose regimen of Coartem Tablets had no effect on systemic exposure of DHA, lumefantrine or quinine in 14 healthy volunteers. Mean AUC of artemether were 46% lower when administered with quinine compared to Coartem Tablets alone. This decrease in artemether exposure is not thought to be clinically significant. However, quinine should be used cautiously in patients following treatment with Coartem Tablets due to the long elimination half-life of lumefantrine and the potential for additive effects on the QT interval [see Warnings and Precautions (5.2)].

Anti-Retroviral Drugs 

No formal drug-drug interaction studies between Coartem Tablets and Anti-Retroviral drugs (ARTs), such as protease inhibitors, non-nucleoside reverse transcriptase inhibitors, have been performed. Due to variable patterns of inhibition, induction or competition for CYP3A4 with anti-retroviral drugs, Coartem Tablets should be used cautiously in patients on ARTs as the result may be an increase in lumefantrine concentrations causing QT prolongation, a decrease in concentrations of the ART resulting in loss of efficacy, or a decrease in artemether and/or lumefantrine concentrations resulting in loss of antimalarial efficacy of Coartem Tablets [see Warnings and Precautions (5.3)].

Hormonal Contraceptives

No formal drug-drug interaction studies between Coartem Tablets and hormonal contraceptives have been performed. However, artemether may induce CYP3A4/5, reducing the effectiveness of hormonal contraceptives [see Warnings and Precautions (5.3)].

Microbiology

Mechanism of Action

Coartem Tablets, a fixed ratio of 1:6 parts of artemether and lumefantrine, respectively, is an antimalarial agent. Artemether is rapidly metabolized into an active metabolite dihydroartemisinin (DHA). The anti-malarial activity of artemether and DHA has been attributed to endoperoxide moiety. The exact mechanism by which lumefantrine, exerts its anti-malarial effect is not well defined. Available data suggest lumefantrine inhibits the formation of β-hematin by forming a complex with hemin. Both artemether and lumefantrine were shown to inhibit nucleic acid and protein synthesis.

Activity In Vitro and In Vivo

Artemether and lumefantrine are active against the erythrocytic stages of Plasmodium falciparum.

Drug Resistance

Strains of P. falciparum with a moderate decrease in susceptibility to artemether or lumefantrine alone can be selected in vitro or in vivo, but not maintained in the case of artemether. The clinical relevance of such an effect is not known.

Effects on the Electrocardiogram

In a healthy adult volunteer parallel group study including a placebo and moxifloxacin control group (n=42 per group), the administration of the 6-dose regimen of Coartem Tablets was associated with prolongation of QTcF (Fridericia). Following administration of a 6-dose regimen of Coartem Tablets consisting of 4 tablets per dose (total of 4 tablets of 80 mg artemether/480 mg lumefantrine) taken with food, the maximum mean change from baseline and placebo adjusted QTcF was 7.5 msec (1-sided 95% Upper CI: 11 msec). There was a concentration-dependent increase in QTcF for lumefantrine.

In clinical trials conducted in children, no patient had QTcF >500 msec. Over 5% of patients had an increase in QTcF of over 60 msec.

In clinical trials conducted in adults, QTcF prolongation of >500 msec was reported in 3 (0.3%) of patients. Over 6% of adults had a QTcF increase of over 60 msec from baseline.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies were not conducted.

Mutagenesis

No evidence of mutagenicity was detected. The artemether: lumefantrine combination was evaluated using the Salmonella and Escherichia/mammalian-microsome mutagenicity test, the gene mutation test with Chinese hamster cells V79, the cytogenetic test on Chinese hamster cells in vitro, and the rat micronucleus test, in vivo. 

Impairment of Fertility

Pregnancy rates were reduced by about one half in female rats dosed for 2 to 4 weeks with the artemether-lumefantrine combination at 1000 mg/kg (about 9 times the clinical dose based on body surface area comparisons). Male rats dosed for 70 days showed increases in abnormal sperm (87 % abnormal) and increased testes weights at 30 mg/kg doses (about one third the clinical dose). Higher doses (about 9 times the clinical dose) resulted in decreased sperm motility and 100 % abnormal sperm cells.

Animal Toxicology and/or Pharmacology

Reproductive Toxicity

Pregnant rats dosed during the period of organogenesis, at or higher than 60 mg/kg/day with the artemether-lumefantrine combination (a dose about half the highest clinical dose based on body surface area comparisons), showed increases in the number of dead fetuses, early resorptions and post implantation losses. No adverse effects were observed in animals dosed at 40 mg/kg (about one third the clinical dose). Similarly, dosing in pregnant rabbits at 175 mg/kg/day (about three times the highest clinical dose based on body surface area comparisons) resulted in abortions, preimplantation losses, post implantation losses, and decreases in the number of live fetuses. No adverse reproductive effects were detected in rabbits at 105 mg/kg/day, about two times the clinical dose based on body surface area comparisons.

Other artemisinins are known to be embryotoxic in animals. Reproductive toxicity studies with artemisinin derivatives (e.g, artesunate) demonstrated increased post-implantation loss and teratogenicity (a low incidence of cardiovascular and skeletal malformations) in rats and rabbits. Similar findings were not seen in animal reproductive studies using artemether.

Neurotoxicity

Studies in dogs and rats have shown that intramuscular injections of artemether resulted in brain lesions. Changes observed mainly in brainstem nuclei included chromatolysis, eosinophilic cytoplasmic granulation, spheroids, apoptosis, and dark neurons. Lesions were observed in rats dosed with artemether at 25 mg/kg for 7 or 14 days and dogs dosed at 20 mg/kg for 8 days or longer, but lesions were not observed after shorter courses of drug or after oral dosing. The estimated artemether 24 h AUC after 7 days of dosing at the no observed effect level (10 mg/kg/day given intramuscularly) is approximately 7-fold greater than the estimated artemether 24 h AUC in humans on day 1 of the standard 3-day oral treatment regimen; oral exposure in humans decreases on subsequent days, thus the exposure margin increases. Dogs dosed orally with 143 mg/kg artemether showed a statistically measureable effect on the hearing threshold at 20 dB. This dose is equivalent to about 29 times the highest artemether clinical dose (160 mg/day) based on body surface area comparisons. Most nervous system disorder adverse events in the studies of the 6-dose regimen were mild in intensity and resolved by the end of the study [see Adverse Reactions (6.2)].

Clinical Studies

Treatment of Acute, Uncomplicated P. falciparum Malaria

The efficacy of Coartem Tablets was evaluated for the treatment of acute, uncomplicated malaria caused by P. falciparum in HIV negative patients in 8 clinical studies. Uncomplicated malaria was defined as symptomatic P. falciparum malaria without signs and symptoms of severe malaria or evidence of vital organ dysfunction. Baseline parasite density ranged from 500/µL - 200,000/µL (0.01% to 4% parasi

Fulvicin-U/F

Generic Name: griseofulvin (Oral route)

gris-ee-oh-FUL-vin

Commonly used brand name(s)

In the U.S.

• Fulvicin P/G


• Fulvicin-U/F


• Grifulvin V


• Gris-PEG

Available Dosage Forms:

• Tablet


• Capsule


• Suspension

Therapeutic Class: Antifungal

Uses For Fulvicin-U/F

Griseofulvin belongs to the group of medicines called antifungals. It is used to treat fungus infections of the body, feet, groin and thighs, scalp, skin, fingernails, and toenails. This medicine may be taken alone or used along with medicines that are applied to the skin for fungus infections.

Use of griseofulvin for prevention of fungus infection have not been established.

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

Before Using Fulvicin-U/F

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 performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of griseofulvin in children. However, safety and efficacy have not been established in children up to 2 years of age.

Geriatric

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

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 taking 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 may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Desogestrel


• Dienogest


• Drospirenone


• Estradiol Cypionate


• Estradiol Valerate


• Ethinyl Estradiol


• Ethynodiol Diacetate


• Etonogestrel


• Levonorgestrel


• Medroxyprogesterone Acetate


• Mestranol


• Norelgestromin


• Norethindrone


• Norgestimate


• Norgestrel


• Phenobarbital


• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

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:

• Actinomycosis (bacterial infection) or


• Blastomycosis (Gilchrist’s disease) or


• Candidiasis (yeast infection) or


• Histoplasmosis (Darling’s disease) or


• Other infections (e.g., bacteria) or


• Sporotrichosis (Rose gardener's disease) or


• Tinea versicolor (Tinea flava)—Griseofulvin will not work in patients with these conditions.

• Liver failure or


• Porphyria (enzyme problem)—Should not be used in patients with these conditions.

• Lupus erythematosus or lupus-like diseases—Use with caution. May make this condition worse.

Proper Use of griseofulvin

This section provides information on the proper use of a number of products that contain griseofulvin. It may not be specific to Fulvicin-U/F. Please read with care.

Keep using this medicine for the full treatment time, even if you feel better after the first few doses. Your infection may not clear up if you stop using the medicine too soon.

Keep yourself clean to help control infection and prevent reinfection.

Griseofulvin is absorbed best when it is taken with a high fat meal, such as a cheeseburger, whole milk, or ice cream. Tell your doctor if you are on a low-fat diet.

Griseofulvin is best taken with or after meals, especially fatty ones (e.g., whole milk or ice cream). This lessens possible stomach upset and helps to clear up the infection by helping your body absorb the medicine better. However, if you are on a low-fat diet, check with your doctor.

For patients taking the oral liquid:

• Use a specially marked measuring spoon or other device to measure each dose accurately. The average household teaspoon may not hold the right amount of liquid.

You may swallow the tablets whole or sprinkle the crushed tablets in one tablespoonful of applesauce. Swallow it immediately without chewing.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (microsize capsules, tablets, or suspension):
  
  • Treatment of fungus infections of the feet and nails:
    
    • Adults and teenagers—500 milligrams (mg) every 12 hours.
    
    
    • Children—Dose is based on body weight and must be determined by your doctor. The usual dose is 5 milligrams (mg) per kilogram (kg) (2.3 mg per pound) of body weight every 12 hours, or 10 milligrams (mg) per kilogram (kg) (4.6 mg per pound) of body weight once a day.
    
    
  
  
  • Treatment of fungus infections of the scalp, skin, and groin:
    
    • Adults and teenagers—250 milligrams (mg) every 12 hours or 500 mg once a day.
    
    
    • Children—Dose is based on body weight and must be determined by your doctor. The usual dose is 5 milligrams (mg) per kilogram (kg) (2.3 mg per pound) of body weight every 12 hours, or 10 milligrams (mg) per kilogram (kg) (4.6 mg per pound) of body weight once a day.
    
    
  
  


• For oral dosage form (ultramicrosize tablets):
  
  • Treatment of fungus infections:
    
    • Adults—375 milligrams (mg) per day, taken as a single dose or divided in small doses. Some patients may need 750 mg divided in small doses.
    
    
    • Children 3 years of age and older weighing over 60 pounds—Dose is based on body weight and must be determined by your doctor. The usual dose is 187.5 to 375 mg per day.
    
    
    • Children 3 years of age and older weighing 35 to 60 pounds—Dose is based on body weight and must be determined by your doctor. The usual dose is 125 to 187.5 mg per day.
    
    
    • Children up to 2 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Fulvicin-U/F

It is very important that your doctor should check the progress of you or your child at regular visits to make sure that this medicine is working properly and to check for unwanted effects.

If your symptoms do not improve, or if they become worse, check with your doctor. You may need to take this medicine for several weeks or months before your infection gets better.

Using this medicine while you are pregnant may cause serious unwanted effects in your newborn baby. Tell your doctor right away if you think you are pregnant or if you plan to become pregnant while using this medicine.

Serious skin reactions can occur with this medicine. Stop using this medicine and check with your doctor right away if you or your child have blistering, peeling, or loosening of the skin; red skin lesions; severe acne or skin rash; sores or ulcers on the skin; or fever or chills while you are using this medicine.

Stop using this medicine and check with your doctor right away if you or your child have pain or tenderness in the upper stomach; pale stools; dark urine; loss of appetite; nausea; unusual tiredness or weakness; or yellow eyes or skin. These could be symptoms of a serious liver problem.

Griseofulvin has been shown to cause liver and thyroid tumors in some animals. You and your doctor should discuss the good this medicine will do, as well as the risks of taking it.

Birth control pills containing estrogen may not work properly if you take them while you are taking griseofulvin. Unplanned pregnancies may occur. To keep from getting pregnant, use another form of birth control for up to 1 month after your last treatment. Other forms of birth control include condoms, diaphragms, or contraceptive foams or jellies.

Griseofulvin may increase the effects of alcohol. If taken with alcohol it may also cause fast heartbeat, flushing, increased sweating, or redness of the face. If you have these symptoms, do not drink alcoholic beverages while you are taking this medicine, unless you have checked first with your doctor.

This medicine may cause some people to become dizzy, drowsy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do other things that could be dangerous if you are dizzy or are not alert. If these reactions are especially bothersome, check with your doctor.

Griseofulvin may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight, even for brief periods of time, may cause a skin rash, itching, redness or other discoloration of the skin, or a severe sunburn. When you begin taking this medicine:

• Stay out of direct sunlight, especially between the hours of 10:00 a.m. and 3:00 p.m., if possible.


• Wear protective clothing, including a hat. Also, wear sunglasses.


• Apply a sun block product that has a skin protection factor (SPF) of at least 15. Some patients may require a product with a higher SPF number, especially if they have a fair complexion. If you have any questions about this, check with your doctor.


• Apply a sun block lipstick that has an SPF of at least 15 to protect your lips.


• Do not use a sunlamp or tanning bed or booth.

If you have a severe reaction from the sun, check with your doctor.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Fulvicin-U/F Side Effects

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

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

More common

• Blistering, peeling, or loosening of the skin


• chills


• cough


• diarrhea


• fever


• itching


• joint or muscle pain


• red, irritated eyes


• sore throat


• sores, ulcers, or white spots in the mouth or on the lips


• unusual tiredness or weakness

Less common

• Confusion


• increased sensitivity of the skin to sunlight


• skin rash, hives, or itching


• soreness or irritation of the mouth or tongue

Rare

• Black, tarry stools


• chest pain


• cloudy urine


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• numbness, tingling, pain, or weakness in the hands or feet


• painful or difficult urination


• shortness of breath


• swollen glands


• unusual bleeding or bruising


• yellow eyes or skin

Incidence not known

• Abdominal or stomach pain


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• clay-colored stools


• dark urine


• dizziness


• headache


• loss of appetite


• nausea


• unpleasant breath odor


• vomiting of blood

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Hives or welts


• redness of the skin

Less common

• Trouble with sleeping

Incidence not known

• Heartburn


• pain or discomfort in the chest, upper stomach, or throat


• sleeplessness


• unable to sleep


• white patches in the mouth or throat or on the tongue


• white patches with diaper rash

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: Fulvicin-U/F side effects (in more detail)

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More Fulvicin-U/F resources

• Fulvicin-U/F Side Effects (in more detail)
• Fulvicin-U/F Use in Pregnancy & Breastfeeding
• Drug Images
• Fulvicin-U/F Drug Interactions
• Fulvicin-U/F Support Group
• 1 Review for Fulvicin-U/F - Add your own review/rating

Compare Fulvicin-U/F with other medications

• Dermatophytosis
• Onychomycosis, Fingernail
• Onychomycosis, Toenail
• Tinea Barbae
• Tinea Capitis
• Tinea Corporis
• Tinea Cruris
• Tinea Pedis