Allegra

Generic Name: fexofenadine (Oral route)

fex-oh-FEN-a-deen

Commonly used brand name(s)

In the U.S.

• Allegra


• Allegra ODT

Available Dosage Forms:

• Tablet


• Tablet, Disintegrating


• Capsule


• Suspension

Therapeutic Class: Respiratory Agent

Pharmacologic Class: Antihistamine, Less-Sedating

Chemical Class: Butyrophenone

Uses For Allegra

Fexofenadine is an antihistamine. It is used to relieve the symptoms of hay fever (seasonal allergic rhinitis) and hives of the skin (chronic idiopathic urticaria) .

Antihistamines work by preventing the effects of a substance called histamine, which is produced by the body. Histamine can cause itching, sneezing, runny nose, and watery eyes. Also, in some people histamine can close up the bronchial tubes (air passages of the lungs) and make breathing difficult. Histamine can also cause some people to have hives, with severe itching of the skin .

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

Do not give any over-the-counter (OTC) cough and cold medicine to a baby or child under 4 years of age. Using these medicines in very young children might cause serious or possibly life-threatening side effects .

Before Using Allegra

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 fexofenadine in children below 6 months of age. Safety and efficacy have not been established .

Do not give any cough and cold medicine to a baby or child under 4 years of age. Using these medicines in very young children might cause serious or possibly life-threatening side effects .

Geriatric

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of fexofenadine in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require an adjustment in the dose for patients receiving fexofenadine .

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 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 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.

• Droperidol

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.

• Aluminum Carbonate, Basic


• Aluminum Hydroxide


• Aluminum Phosphate


• Dihydroxyaluminum Aminoacetate


• Dihydroxyaluminum Sodium Carbonate


• Magaldrate


• Magnesium Carbonate


• Magnesium Hydroxide


• Magnesium Oxide


• Magnesium Trisilicate


• 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. 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 may cause an increased risk of certain side effects 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.

• Apple Juice


• Grapefruit Juice


• Orange Juice

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:

• Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body .

• Phenylketonuria—Use with caution. The oral disintegrating tablets contain phenylalanine .

Proper Use of fexofenadine

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

You should always take this medicine with water. Do not take it with juice such as grapefruit, orange, or apple juice .

You should NOT take antacids that contain aluminum or magnesium hydroxide within 15 minutes of taking this medicine. If you are uncertain about this, ask your doctor or pharmacist .

For patients using the oral disintegrating tablet form of this medicine:

• Make sure your hands are dry.


• Do not push the tablet through the foil backing of the package. Instead, gently peel back the foil backing and remove the tablet.


• Immediately place the tablet on top of the tongue. Do not chew or break the tablet.


• The tablet will dissolve in seconds, and you may swallow it with your saliva. You may drink a glass of water after the tablet has dissolved.


• Always take this tablet on an empty stomach .

Shake the oral liquid well before using it. Measure the liquid with a marked measuring spoon, oral syringe, or medicine cup .

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 symptoms of hay fever:
  
  • For oral dosage form (capsules, tablets):
    
    • Adults and children 12 years of age and older—60 milligrams (mg) two times a day, or 180 mg once a day.
    
    
    • Children 6 to 11 years of age—30 mg two times a day.
    
    
    • Children 4 to 6 years of age—Use and dose must be determined by your doctor .
    
    
    • Children and infants up to 4 years of age—Use is not recommended .
    
    
  
  
  • For oral dosage form (disintegrating tablets):
    
    • Children 6 to 11 years of age—30 milligrams (mg) two times a day, on an empty stomach.
    
    
    • Children 4 to 6 years of age—Use and dose must be determined by your doctor .
    
    
    • Children and infants up to 4 years of age—Use is not recommended .
    
    
  
  
  • For oral dosage form (suspension):
    
    • Children 4 to 11 years of age—30 milligrams (mg) or 5 milliliters (mL) two times a day.
    
    
    • Children younger than 4 years of age—Use and dose must be determined by your doctor .
    
    
  
  

• For symptoms of chronic hives:
  
  • For oral dosage form (capsules, tablets):
    
    • Adults and children 12 years of age and older—60 milligrams (mg) two times a day, or 180 mg once a day.
    
    
    • Children 4 to 11 years of age—30 mg two times a day.
    
    
    • Children younger than 4 years of age—Use and dose must be determined by your doctor .
    
    
  
  
  • For oral dosage form (disintegrating tablets):
    
    • Children 4 to 11 years of age—30 milligrams (mg) two times a day, on an empty stomach.
    
    
    • Children younger than 4 years of age—Use and dose must be determined by your doctor .
    
    
  
  
  • For oral dosage form (suspension):
    
    • Children 4 to 11 years of age—30 milligrams (mg) or 5 milliliters (mL) two times a day.
    
    
    • Children 6 months to 4 years of age—15 mg or 2.5 mL two times a day.
    
    
    • Children younger than 6 months 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 Allegra

It is important that your doctor check your progress at regular visits to allow for changes in your dose and to help reduce any side effects .

Allegra 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:

Rare

• Chest tightness


• feeling of warmth, redness of the face, neck, arms and occasionally, upper chest


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


• shortness of breath, difficult or labored breathing

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

• Vomiting

Less common

• Back pain


• body aches or pain


• chills


• coughing


• diarrhea


• difficulty with moving


• dizziness


• ear congestion


• earache


• fever


• headache


• joint pain


• loss of voice


• muscle aching or cramping


• muscle pains or stiffness


• nasal congestion


• nausea


• pain in arms or legs


• pain or tenderness around eyes or cheekbones


• painful menstrual bleeding


• redness or swelling in ear


• ringing or buzzing in ears


• runny or stuffy nose


• sleepiness or unusual drowsiness


• sneezing


• sore throat


• stomach upset


• swollen joints


• unusual feeling of tiredness or weakness


• viral infection (such as cold and flu)

Rare

• Nervousness


• rash


• sleeplessness


• terrifying dreams


• trouble sleeping

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: Allegra side effects (in more detail)

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

More Allegra resources

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

• Allegra Prescribing Information (FDA)


• Allegra Monograph (AHFS DI)


• Allegra Consumer Overview


• Allegra MedFacts Consumer Leaflet (Wolters Kluwer)


• Fexofenadine Prescribing Information (FDA)


• Allegra ODT Orally Disintegrating Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Allegra with other medications

• Hay Fever
• Urticaria

Imatinib Mesylate

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 4 - [(4 - methyl - 1 - piperazinyl)methyl] - N - [4 - methyl - 3 - [[4 - (3 - pyridinyl) - 2 - pyrimidinyl]aminophenyl] - benzamide methanesulfonate salt
CAS Number: 152459-95-5
Brands: Gleevec

Introduction

Antineoplastic agent; an inhibitor of Bcr-Abl tyrosine kinase.¹

Uses for Imatinib Mesylate

Chronic Myelogenous Leukemia (CML)

First-line treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) CML in adult and pediatric patients who are in the chronic phase of the disease (designated an orphan drug by FDA for this use);^{1 4 18} follow-up is limited.¹

Second-line treatment of Ph+ CML in adults who are in blast crisis, in the accelerated phase, or in the chronic phase of the disease after failure of interferon alfa therapy (designated an orphan drug by FDA for this use).^{1 4 10}

Second-line treatment of pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplantation or who are resistant to interferon alfa therapy.¹

Efficacy in pediatric patients determined based on overall hematologic and/or cytogenetic response rates; actual clinical benefits (e.g., decrease in disease-related symptoms, increase in survival) not adequately studied.^{1 a}

Acute Lymphocytic Leukemia (ALL)

Treatment of relapsed or refractory Ph+ ALL in adults (designated an orphan drug by FDA for this use).^{4 20 a}

Myelodysplastic Syndrome (MDS) or Myeloproliferative Disease (MPD)

Treatment of MDS or MPD associated with gene rearrangements of platelet-derived growth factor receptor (PDGFR) in adults (designated an orphan drug by FDA for this use).^{4 20 a}

Systemic Mastocytosis (SM)

Treatment of aggressive systemic mastocytosis (ASM) in adults who lack the D816V c-Kit mutation or in whom c-Kit mutational status is unknown (designated an orphan drug by FDA for this use).^{4 20 a}

Ineffective for ASM with the D816V c-Kit mutation; other therapy is indicated.^{8 a 20}

Has not been shown to be effective in patients with less aggressive forms of SM.^a Therefore, not recommended for use in patients with cutaneous mastocytosis, indolent SM (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematologic non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma, or extracutaneous mastocytoma.^a

Hypereosinophilic Syndrome (HES) or Chronic Eosinophilic Leukemia (CEL)

Treatment of HES and/or CEL in adults who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion), patients who are negative for FIP1L1-PDGFRα fusion kinase, or patients in whom expression of FIP1L1-PDGFRα fusion kinase is unknown (designated an orphan drug by FDA for this use).^{4 20 a}

Dermatofibrosarcoma Protuberans (DFSP)

Treatment of unresectable, recurrent, and/or metastatic DFSP in adults (designated an orphan drug by FDA for this use).^{4 20 a}

GI Stromal Tumors (GIST)

Treatment of patients with Kit (CD117)-positive unresectable and/or metastatic malignant GIST (designated an orphan drug by FDA for this use).^{1 4 18}

Efficacy determined based on objective response rates; actual clinical benefits (e.g., decrease in disease-related symptoms, increase in survival) not adequately studied.¹

Imatinib Mesylate Dosage and Administration

General

• 
  

  Use under supervision of a qualified clinician experienced in the treatment of hematologic malignancies or malignant sarcomas.¹

  
  


• 
  

  In patients with elevated eosinophil concentrations, consider prophylactic use of systemic corticosteroids for 1–2 weeks concomitantly with imatinib upon initiation of therapy to reduce the risk of hypereosinophilic cardiac toxicity.²⁰ (See Cardiovascular Effects under Cautions.)

  
  


• 
  

  Therapy may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.¹

  
  

Administration

Oral Administration

Administer once or twice daily with a meal and a large glass (240 mL) of water to minimize gastric irritation.^{1 8 10}

In adults, administer doses of 400 or 600 mg once daily; dosages of 800 mg should be administered as 400 mg twice daily using the 400-mg tablet to reduce exposure to iron.¹

In children or adolescents, administer once daily; alternatively, administer in 2 equally divided doses in the morning and evening.¹

For patients unable to swallow the film-coated tablets, place required number of tablets in the appropriate volume (approximately 50 mL for a 100-mg tablet and 200 mL for a 400-mg tablet) of water or apple juice; stir with a spoon.¹ Administer the suspension immediately after complete disintegration of the tablet(s).^{1 8 10}

Dosage

Available as imatinib mesylate; dosage expressed in terms of imatinib.¹

Pediatric Patients

CML

First-line Treatment of Ph+ CML in Chronic Phase

Oral

Children >2 years of age: 340 mg/m² given once daily or in 2 equally divided doses (once in the morning and once in the evening), not to exceed 600 mg daily.¹

Second-line Treatment of Ph+ CML in Chronic Phase

Oral

Children >2 years of age: 260 mg/m² given once daily or in 2 equally divided doses (once in the morning and once in the evening).¹

Adults

CML

First- or Second-line Treatment of Ph+ CML in Chronic Phase

Oral

400 mg daily.^{1 10} If there is evidence of disease progression (at any time), inadequate hematologic response after at least 3 months of therapy, inadequate cytogenetic response after 6–12 months of therapy, or loss of a previously achieved hematologic or cytogenetic response, may increase dosage (in the absence of severe adverse drug or hematologic effects) to 600 mg daily.^{1 10} In the randomized trial, further dose escalation (to 800 mg daily, administered as 400 mg twice daily) was permitted.¹

Second-line Treatment of Ph+ CML in Accelerated Phase or Blast Crisis

Oral

600 mg daily.^{1 10} If there is evidence of disease progression (at any time), inadequate hematologic response after at least 3 months of therapy, inadequate cytogenetic response after 6–12 months of therapy, or loss of a previously achieved hematologic or cytogenetic response, may increase dosage (in the absence of severe adverse drug or hematologic effects) to 800 mg daily (administered as 400 mg twice daily).^{1 10}

ALL

Oral

600 mg daily.^{20 a}

MDS/MPD

Oral

400 mg daily.^{20 a}

ASM

Oral

ASM without D816V c-Kit mutation: 400 mg daily.^{20 a}

ASM with unknown D816V c-Kit mutational status not responding satisfactorily to other therapies: May consider dosage of 400 mg daily.^{20 a}

ASM (without D816V c-Kit mutation or with unknown D816V c-Kit mutational status) that is associated with eosinophilia (a clonal hematologic disease related to the FIP1L1-PDGFRα fusion kinase): Initially, 100 mg daily; if therapeutic response is insufficient, may increase dosage to 400 mg daily as tolerated.^{8 20 a}

HES/CEL

Oral

HES/CEL with FIP1L1-PDGFRα fusion kinase expression: Initially, 100 mg daily; if therapeutic response is insufficient, may increase dosage to 400 mg daily as tolerated.^{20 a}

HES/CEL in patients without FIP1L1-PDGFRα fusion kinase expression or in patients in whom expression of FIP1L1-PDGFRα fusion kinase is unknown: 400 mg daily.^{8 20 a}

DFSP

Oral

800 mg daily.^{20 a}

GIST

Oral

400 or 600 mg once daily.¹

Dosage Modification for Toxicity

Dermatologic Toxicity

If severe dermatologic toxicity (e.g., bullous skin reactions) occurs, discontinue imatinib.¹ Reinitiation of imatinib therapy has been tolerated in some patients when the drug was reinitiated at a lower dosage (with or without corticosteroids or antihistamines) following resolution or lessening of the bullous skin reaction.¹

Fluid Retention/Edema

Management of edema may include diuretics, other supportive measures, and/or reduction of imatinib dosage.¹ If severe fluid retention or edema develops, interrupt imatinib therapy until complete resolution occurs.¹

Hepatic Toxicity

If substantial increases in bilirubin (>3 times ULN) or hepatic transaminase concentrations (>5 times ULN) occur, withhold imatinib until bilirubin or transaminase concentrations decrease to <1.5 or <2.5 times ULN, respectively.¹ Resume therapy at a reduced daily dosage.¹ Adults previously receiving a dosage of 400, 600, or 800 mg daily may resume therapy at a dosage of 300, 400, or 600 mg daily, respectively;^{1 8} pediatric patients previously receiving a dosage of 260 or 340 mg/m² daily may resume therapy at a dosage of 200 or 260 mg/m² daily, respectively.¹

Hematologic Toxicity

Adjust dosage or interrupt therapy if severe neutropenia and/or thrombocytopenia occurs (see tables below).¹

Pediatric Patients >2 Years of Age: Dosage Adjustments for Neutropenia and Thrombocytopenia

Use (Initial Dosage)	Hematologic Measurements	Comments
Newly diagnosed chronic phase Ph+ CML (initial dosage: 340 mg/m2 daily)	ANC <1000/mm3 and/or platelets <50,000/mm3	1. Discontinue imatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm31 2. Resume imatinib at previous dosage (i.e., before severe adverse reaction occurred)1 3. If recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3 occurs, repeat step 1 and resume therapy at a reduced dosage of 260 mg/m21 a
Recurrent or resistant chronic phase Ph+ CML (initial dosage: 260 mg/m2 daily)	ANC <1000/mm3 and/or platelets <50,000/mm3	1. Discontinue imatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm31 2. Resume imatinib at previous dosage (i.e., before severe adverse reaction occurred)1 3. If recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3 occurs, repeat step 1 and resume therapy at a reduced dosage of 200 mg/m21 a

Adults: Dosage Adjustments for Neutropenia and Thrombocytopenia

Use (Initial Dosage)	Hematologic Measurements	Comments
ASM associated with eosinophilia (initial dosage: 100 mg daily)20 a or HES/CEL with FIP1L1- PDGFRα fusion kinase expression (initial dosage: 100 mg daily)20 a	ANC <1000/mm3 and/or platelets <50,000/mm3	1. Discontinue imatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm320 a 2. Resume imatinib at previous dosage (i.e., before severe adverse reaction occurred)20 a
Chronic phase Ph+ CML (initial dosage: 400 mg daily) or MDS/MPD, ASM, or HES/CEL (initial dosage: 400 mg daily)20 a or GIST (initial dosage: 400 or 600 mg daily)	ANC <1000/mm3 and/or platelets <50,000/mm3	1. Discontinue imatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm31 20 2. Resume imatinib at original dosage of 400 or 600 mg once daily1 3. If recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3 occurs, repeat step 1 and resume therapy at a reduced dosage (reduce from 400 mg to 300 mg or from 600 mg to 400 mg once daily)1
Ph+ CML: Accelerated phase and blast crisis (initial dosage: 600 mg daily) or Ph+ ALL (initial dosage: 600 mg daily)20 a	ANC <500/mm3 and/or platelets <10,000/mm3	1. If cytopenia is unrelated to leukemia (as determined by marrow aspirate or biopsy), reduce dosage to 400 mg once daily1 20 2. If cytopenia persists for 2 weeks, further reduce dosage to 300 mg once daily1 3. If cytopenia persists for 4 weeks and still is unrelated to CML, withhold therapy until ANC ≥1000/mm3 and platelets ≥20,000/mm3; then reinitiate therapy at 300 mg once daily1
DFSP (initial dosage: 800 mg daily)20 a	ANC <1000/mm3 and/or platelets <50,000/mm3	1. Discontinue imatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm320 a 2. Resume imatinib at dosage of 600 mg once daily20 a 3. If recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3 occurs, repeat step 1 and resume therapy at a reduced dosage of 400 mg once daily20 a

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment: Initially, up to 400 mg daily.¹ In patients with conditions normally requiring initial dosages <400 mg daily (e.g., pediatric patients with small body frame, adults with ASM or HES/CEL with FIP1L1-PDGFRα fusion kinase expression), start therapy at recommended initial dosage, regardless of hepatic function.⁸ (See Dosage under Dosage and Administration.)

Severe hepatic impairment: Initially, up to 300 mg daily.¹ In patients with conditions normally requiring initial dosages <300 mg daily (e.g., pediatric patients with small body frame, adults with ASM or HES/CEL with FIP1L1-PDGFRα fusion kinase expression), start therapy at recommended initial dosage, regardless of hepatic function.⁸ (See Dosage under Dosage and Administration.) In adult patients with ASM or HES/CEL with FIP1L1-PDGFRα fusion kinase expression who require dosage escalation, initially, increase dosage from 100 mg daily to 300 mg daily (rather than to 400 mg daily as usually recommended) and monitor liver function carefully; if therapeutic response is insufficient, consider increasing dosage to 400 mg daily as tolerated.⁸

Patients Receiving Potent CYP3A4 Inducers

Increase imatinib dosage by at least 50% and carefully monitor clinical response in patients receiving concomitant therapy with imatinib and potent CYP3A4 inducers (e.g., phenytoin, rifampin).¹ (See Interactions.)

Cautions for Imatinib Mesylate

Contraindications

• 
  

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

  
  

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;¹ teratogenicity and embryolethality demonstrated in animals.¹ Avoid pregnancy during therapy.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Major Toxicities

Dermatologic Effects

Bullous skin reactions, including erythema multiforme and Stevens-Johnson syndrome, reported.¹ If dermatologic toxicity occurs, discontinue imatinib.¹ Has been reinitiated in some patients at a reduced dosage (with or without concomitant corticosteroids or antihistamines) following resolution or lessening of the bullous skin reaction.¹

Fluid Retention and Edema

Risk of severe superficial edema (e.g., rapid weight gain, facial edema, anasarca),^{1 5 6} severe fluid retention (i.e., pleural effusion, pericardial effusion, pulmonary edema, ascites),^{1 8 10} cardiac tamponade, cerebral edema, increased intracranial pressure, and papilledema (including fatalities).¹

The incidence of edema and fluid retention appears to be increased in CML patients in blast crisis, in patients receiving higher dosages (i.e., 600 mg daily), and in geriatric patients.¹

Monitor signs (e.g., body weight) and symptoms of fluid retention regularly.¹ If severe fluid retention develops, withhold imatinib therapy and provide appropriate treatment until complete resolution occurs.¹

GI Effects

Nausea, vomiting, and diarrhea occur frequently.¹ GI perforation, sometimes fatal, reported rarely.¹

Administer with food and a large glass of water to minimize GI irritation.¹

Hemorrhage

Risk of grade 3 or 4 hemorrhage, GI bleeds, and/or intratumoral bleeds.¹ GI bleeds may have originated from GI tumor sites.¹

Hematologic Effects

Risk of grade 3 or 4 neutropenia,^{1 5 8} anemia, or thrombocytopenia.^{1 5 8} Cytopenias reported less frequently in patients with newly diagnosed CML; higher frequency of grade 3 or 4 neutropenia and thrombocytopenia in patients with blast crisis or accelerated phase CML than in patients with chronic phase CML.¹ In pediatric patients with CML, grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) usually occurred within the first several months of therapy.¹

Monitor CBCs weekly during the first month of therapy, every other week during the second month, and periodically (e.g., every 2–3 months) thereafter as clinically indicated.¹ If hematologic toxicity occurs, withhold therapy.¹ (See Hematologic Toxicity under Dosage and Administration.)

Hepatic Effects

Risk of grade 3 or 4 hyperbilirubinemia and elevations in alkaline phosphatase, ALT, and AST (grade 3 or 4 severity).^{1 10} Fatal hepatic failure occurred in at least one patient who received imatinib concomitantly with acetaminophen.^{1 8}

Monitor liver function tests (i.e., transaminases, bilirubin, alkaline phosphatase) prior to initiation of therapy and monthly thereafter or as clinically indicated.¹ If liver function test results are abnormal, withhold imatinib and/or reduce imatinib dosage.¹ (See Hepatic Toxicity under Dosage and Administration.)

Cardiovascular Effects

Severe CHF and left ventricular dysfunction reported, mostly in geriatric patients or patients with a history of cardiac disease.^{1 17} Monitor such patients carefully; evaluate and treat any patient with manifestations of cardiac failure.^{1 17}

In patients with HES and cardiac involvement, initiation of imatinib has been associated with cardiogenic shock or left ventricular dysfunction;^{20 a} this condition reportedly was reversible with administration of systemic corticosteroids, circulatory support measures, and temporary discontinuance of imatinib.^a Consider performing echocardiogram and determining serum troponin concentration in patients with elevated eosinophil concentrations (including patients with HES/CEL or patients with MDS/MPD or ASM associated with high eosinophil concentrations).^{20 a} If either is abnormal, consider prophylactic use of systemic corticosteroids for 1–2 weeks concomitantly with imatinib upon initiation of therapy.^{20 a}

Metabolic Effects

Hypophosphatemia associated with altered bone and mineral metabolism has been reported in patients receiving imatinib for CML or GIST.^{1 21}

General Precautions

Long-term Therapy

Consider potential toxicities suggested by animal studies, specifically, hepatic and renal toxicity and immunosuppression.¹ Severe hepatic and renal toxicity observed in animals receiving imatinib for as little as 2 weeks.¹ Immunosuppression reported in animals receiving imatinib for up to 39 weeks.¹

Cardiomyopathy (e.g., cardiac hypertrophy and dilatation, resulting in cardiac insufficiency), chronic progressive nephropathy, and preputial gland papilloma reported in animals receiving imatinib for up to 2 years.^a

Specific Populations

Pregnancy

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

Lactation

Distributed into milk in rats; drug concentration approximately threefold higher in milk than in plasma.¹ Discontinue nursing because of potential risk in nursing infants.¹

Pediatric Use

Safety and efficacy demonstrated only in children with newly diagnosed, recurrent, or resistant Ph⁺ chronic phase CML.¹ The overall safety profile in 93 pediatric patients studied was similar to that in adult patients; however, musculoskeletal pain occurred less frequently in pediatric patients than in adults, and peripheral edema was not reported.¹ Most frequently reported adverse effects include nausea and vomiting.^{1 a}

No data in children <2 years of age.¹

Geriatric Use

In patients with CML, no substantial differences in safety and efficacy relative to younger patients were observed, with the exception of a higher incidence of edema.¹ Formal evaluation has not been performed in patients with GIST, but no obvious differences in safety and efficacy relative to younger patients observed.¹

Hepatic Impairment

Increased exposure to imatinib and its major active metabolite observed in patients with severe hepatic impairment.¹ Close monitoring recommended in these patients.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Safety and efficacy not established; use with caution.^{1 8}

Common Adverse Effects

In patients with CML,¹ nausea,^{1 8 10} vomiting,^{1 8 10} diarrhea,^{1 8 10} edema,^{1 8 10} muscle cramps,^{1 10} musculoskeletal pain,¹ rash.¹

In patients with ALL,^a adverse effects similar to those reported in patients with CML (e.g., mild nausea,^a vomiting,^a diarrhea,^a myalgia,^a muscle cramps,^a rash).^a

In patients with MDS/MPD, nausea,^a diarrhea,^a muscle cramp,^a anemia,^a fatigue,^a arthralgia,^a periorbital edema.^a

In patients with ASM, diarrhea,^a nausea,^a ascites,^a muscle cramps,^a dyspnea,^a fatigue,^a peripheral edema,^a anemia,^a pruritus,^a rash,^a lower respiratory tract infection.^a

In patients with HES/CEL, adverse effects similar to those reported in patients with other hematologic malignancies (e.g., GI/cutaneous/musculoskeletal disorders).^a

In patients with DFSP, nausea,^a fatigue,^a periorbital edema,^a peripheral edema,^a ocular edema,^a diarrhea,^a vomiting,^a rash,^a increased lacrimation,^a anemia,^a facial edema,^a pyrexia,^a exertional dyspnea,^a rhinitis,^a anorexia.^a

In patients with GIST,¹ edema,^{1 8 10} nausea,^{1 8 10} diarrhea,^{1 8 10} abdominal pain,¹ muscle cramps,^{1 10} fatigue,¹ rash.^{1 5 6 8 10}

Other adverse effects occurring in ≥10% of patients: GI/CNS/tumor hemorrhage,¹ headache,¹ dyspepsia,^{1 8} joint pain,¹ weight increase,¹ cough,¹ flatulence,¹ constipation,¹ nasopharyngitis,¹ pharyngolaryngeal pain,¹ night sweats,¹ pruritus,¹ hypokalemia,¹ pneumonia,¹ upper respiratory tract infection,¹ dizziness,¹ insomnia,¹ depression,¹ rigors,¹ back pain,¹ asthenia,¹ influenza,¹ taste disturbance,¹ anxiety,¹ liver toxicity,¹ chest pain,¹ sinusitis,¹ loose stools.¹

The incidence of neutropenia and grade 1 or 2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue appears to be higher in women than in men.¹

Interactions for Imatinib Mesylate

Metabolized principally by CYP3A4 and to a lesser degree by CYP1A2, CYP2D6, CYP2C9, and CYP2C19.¹

Appears to inhibit CYP3A4, CYP2C9, and CYP2D6.¹

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (decreased imatinib metabolism and increased plasma imatinib concentrations).^{1 10}

Inducers of CYP3A4: Potential pharmacokinetic interaction (increased imatinib metabolism and decreased plasma imatinib concentrations).^{1 10}

Drugs Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased plasma concentrations of substrates of CYP3A4, CYP2C9, and CYP2D6).¹

Specific Drugs

Drug	Interaction	Comments
Acetaminophen	Possible increased serum acetaminophen concentrations1 8 Fatal hepatic failure reported in at least one patient 1 8	Use concomitantly with caution1 8
Antifungals, azoles (itraconazole, ketoconazole)	Decreased imatinib metabolism and increased plasma imatinib concentrations1
Benzodiazepines (i.e., triazolo)	Increased benzodiazepine concentrations1
Calcium channel blockers (i.e., dihydropyridines)	Increased calcium channel blocker concentrations1
Carbamazepine	Increased imatinib metabolism and decreased plasma imatinib concentrations1 10	Consider choosing other agents with less enzyme induction potential1
Cyclosporine	Increased cyclosporine concentrations1	Use with caution since cyclosporine has a narrow therapeutic window1
Dexamethasone	Increased imatinib metabolism and decreased plasma imatinib concentrations1 10	Consider choosing other agents with less enzyme induction potential1
HMG-CoA reductase inhibitors (statins) (simvastatin)	Increased statin concentrations1
Macrolide antibiotics (clarithromycin, erythromycin)	Decreased imatinib metabolism and increased plasma imatinib concentrations1
Phenobarbital	Increased imatinib metabolism and decreased plasma imatinib concentrations1 10	Consider choosing other agents with less enzyme induction potential1
Phenytoin	Increased imatinib metabolism and decreased plasma imatinib concentrations1 10	Increase imatinib dosage by at least 50% and monitor clinical response carefully; alternatively, consider choosing other agents with less enzyme induction potential1
Pimozide	Increased pimozide concentrations1	Use with caution since pimozide has a narrow therapeutic window1
Rifampin	Increased imatinib metabolism and decreased peak plasma concentration and AUC of imatinib1 10	Increase imatinib dosage by at least 50% and carefully monitor clinical response; alternatively, consider choosing other agents with less enzyme induction potential1
St. John’s wort	Increased imatinib metabolism and decreased plasma imatinib concentrations1 10	Consider choosing other agents with less enzyme induction potential1
Warfarin	Potential pharmacokinetic and pharmacologic interaction (enhanced anticoagulant effect)1	Patients requiring anticoagulation therapy should receive heparin or low molecular weight heparin1

Imatinib Mesylate Pharmacokinetics

The pharmacokinetics of imatinib are similar in CML and GIST patients.¹

Absorption

Bioavailability

Well absorbed following oral administration.¹ Mean absolute bioavailability is 98%.¹

Following oral administration, peak plasma concentrations are attained within 2–4 hours in adult and pediatric patients.¹ When dosed once daily, accumulation is 1.5–2.5-fold at steady state.¹

Administration of 260 mg/m² or 340 mg/m² in pediatric patients achieved an AUC similar to that attained with a 400-mg dose in adults.¹ Mean imatinib AUC increases proportionally with dose in adults but not in pediatric patients.¹

Special Populations

In patients with severe hepatic impairment, increased peak plasma concentration and AUC of imatinib and its major active metabolite have been observed.¹ (See Hepatic Impairment under Dosage and Administration.)

In patients with mild or moderate hepatic impairment, exposure to imatinib and its major active metabolite was comparable to that in patients with normal hepatic function.¹

Distribution

Extent

Distributed into milk in animals; not known whether the drug or its metabolites are distributed into human milk.¹

Plasma Protein Binding

Approximately 95% (mainly albumin and α₁-acid glycoprotein).¹ Plasma protein binding of major active metabolite is similar to that of the parent drug.¹

Elimination

Metabolism

Metabolized in the liver, principally by CYP3A4 and to a lesser degree by CYP1A2, CYP2D6, CYP2C9, and CYP2C19.¹ The major active metabolite is the N-desmethyl derivative, which has an in vitro potency similar to the parent drug.¹

Elimination Route

Predominantly in feces, mostly as metabolites.¹ Following oral administration of a single radiolabeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days (68% of the dose in feces and 13% of the dose in urine); unchanged drug accounted for 25% of the dose (20% in feces, 5% in urine), the remainder being metabolites.¹

Apparent oral clearance appears to be similar in adults and pediatric patients.¹

Half-life

Approximately 18 hours for imatinib and 40 hours for its major active metabolite in adults; the elimination half-lives in pediatric patients appear to be similar to those in adults.¹

Special Populations

Clearance appears to increase with increasing body weight; no initial dosage adjustment necessary but close monitoring of treatment-related toxicity recommended.¹

Stability

Storage

Oral

Tablets

Tight container at 25°C (may be exposed to 15–30°C).¹ Protect from moisture.¹

ActionsActions

• 
  

  Competitively inhibits Bcr-Abl tyrosine kinase,⁵ the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML.¹¹

  
  

• 
  

  Inhibits proliferation and induces apoptosis of Bcr-Abl-positive cell lines as well as fresh leukemic cells from Ph+ CML.¹ Inhibits tumor growth of Bcr-Abl transfected murine myeloid cells as well as Bcr-Abl-positive leukemia lines derived from CML patients in blast crisis in vivo.¹

  
  

• 
  

  Inhibits receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF-mediated and SCF-mediated cellular events.^{1 8} Inhibits proliferation and induces apoptosis of GIST cells (which express an activating c-kit mutation) in vitro.¹

  
  

Advice to Patients

• 
  

  Risk of severe fluid retention, cytopenia, hepatotoxicity, and adverse dermatologic or cardiovascular effects.¹

  
  

• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity of advising women to avoid pregnancy and nursing during therapy.¹ Advise pregnant women of risk to the fetus.¹

  
  

• 
  

  Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiac disease).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.

Imatinib Mesylate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	100 mg (of imatinib)	Gleevec (scored)	Novartis
		400 mg (of imatinib)	Gleevec (scored)	Novartis

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.

Gleevec 100MG Tablets (NOVARTIS): 30/$1400.05 or 90/$4167.89

Gleevec 400MG Tablets (NOVARTIS): 30/$5040.25 or 60/$9910.53

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.

References

1. Novartis Pharmaceuticals Corporation. Gleevec (imatinib mesylate) tablets prescribing information. East Hanover, NJ; 2006 Sep.

2. Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Investig. 2000; 105:3-7. [PubMed 10619854]

3. McGuire TR, Kazakoff PW. Chronic leukemias. In: DiPiro JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiologic approach. 4th ed. Stamford: Appleton and Lange; 1999:2169-80.

4. Food and Drug Administration. List of orphan designations and approvals. From FDA web site.

5. Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001; 344:1031-7. [IDIS 461596] [PubMed 11287972]

6. Druker BJ, Sawyers CL, Kantarjian H et al. Activity of a specific inhibitor of the Bcr-Abl tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001; 344:1038-42. [IDIS 461597] [PubMed 11287973]

7. Joensuu H, Roberts PJ, Sarlomo-Rikala M. Effect of the tyrosine kinase inhibitor STI571 in a patient with a

Znlin

Generic Name: zinc oxide topical (ZINK OX ide)

Brand Names: ARC, Balmex, Boudreaux Butt Paste, Caldesene, Calmol-4 Suppository, Critic-Aid Skin Paste, Delazinc, Dermagran BC, Desitin, Desitin Maximum Strength Original, Desitin Rapid Relief Creamy, Diaper Rash Ointment, Diaper Relief, Dr. Smith's Diaper, Flanders Buttocks Ointment, Geri-Protect, Medi-Paste, PeriGuard, Pinxav, Rash Relief, RVPaque, Seniortopix Healix, Soothe & Cool Skin Paste, Sportz Block Dark, Sportz Block Light, Sportz Block Medium, Triple Paste, Tronolane Suppositories, Unna-Flex Elastic Unna Boot 3 inch, Unna-Flex Elastic Unna Boot 4 inch, Znlin

What is Znlin (zinc oxide topical)?

Zinc oxide is a mineral.

Zinc oxide topical (for the skin) is used to treat diaper rash, minor burns, severely chapped skin, or other minor skin irritations.

Zinc oxide rectal suppositories are used to treat itching, burning, irritation, and other rectal discomfort caused by hemorrhoids or painful bowel movements.

Zinc oxide topical may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Znlin (zinc oxide topical)?

You should not use this medication if you are allergic to zinc, dimethicone, lanolin, cod liver oil, petroleum jelly, parabens, mineral oil, or wax.

Zinc oxide topical will not treat a bacterial or fungal infection. Call your doctor if you have any signs of infection such as redness and warmth or oozing skin lesions.

Keep the diaper area clean and dry to prevent worsening of skin rash. Change wet diapers as soon as possible. Allow the skin to dry thoroughly before putting on a fresh diaper.

Stop using this medication and call your doctor if your condition does not improve within 7 days of treatment. Avoid getting this medication in your mouth or eyes. If this does happen, rinse with water right away. Do not use zinc oxide topical on deep skin wounds or severe burns. Get medical attention for more severe skin irritation or injury.

Avoid using other medications on the areas you treat with zinc oxide unless you doctor tells you to.

What should I discuss with my health care provider before using Znlin (zinc oxide topical)?

You should not use this medication if you are allergic to zinc, dimethicone, lanolin, cod liver oil, petroleum jelly, parabens, mineral oil, or wax.

Zinc oxide topical will not treat a bacterial or fungal infection. Call your doctor if you have any signs of infection such as redness and warmth or oozing skin lesions.

It is not known whether zinc oxide topical will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether zinc oxide topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without medical advice if you are breast-feeding a baby.

How should I use Znlin (zinc oxide topical)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Apply enough of this medication to cover the entire area to be treated. Zinc oxide often leaves a thin white residue that may not be entirely rubbed in.

To treat chapped skin, minor burn wounds, or other skin irritations, use the medication as often as needed. Apply a thin layer to the affected area and rub in gently.

To treat diaper rash, use this medication each time the diaper is changed. It is especially important to apply the medication at bedtime or whenever there will be a long period of time between diaper changes.

Keep the diaper area clean and dry to prevent worsening of skin rash. Change wet diapers as soon as possible. Allow the skin to dry thoroughly before putting on a fresh diaper.

When using the powder form of this medicine, pour the powder slowly to avoid a large puff into the air. Do not allow a baby to handle a powder bottle during use. Always close the lid after using the powder.

Zinc oxide rectal suppositories come with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Wash your hands before and after inserting a rectal suppository.

Try to empty your bowel and bladder just before using the suppository. Cleanse and dry your rectal area thoroughly.

Remove the outer wrapper from the suppository before inserting it. Avoid handling the suppository too long or it will melt in your hands.

For best results, stay lying down after inserting the suppository and hold it in your rectum for a few minutes. The suppository will melt quickly once inserted and you should feel little or no discomfort while holding it in.

Stop using this medication and call your doctor if your condition does not improve within 7 days of treatment. Store at room temperature away from moisture and heat. Keep the tube cap tightly closed when not in use. You may store zinc oxide rectal suppositories in a refrigerator to prevent melting.

What happens if I miss a dose?

Since zinc oxide is used on an as needed basis, you are not likely to miss a dose. Using extra zinc oxide to make up a missed dose will not make the medication more effective.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while using Znlin (zinc oxide topical)?

Avoid getting this medication in your mouth or eyes. If this does happen, rinse with water right away. Do not use zinc oxide topical on deep skin wounds or severe burns. Get medical attention for more severe skin irritation or injury.

Znlin (zinc oxide topical) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using zinc oxide rectal suppositories if you have rectal bleeding or continued pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Znlin (zinc oxide topical)?

Avoid applying other skin medications on the same treatment area with zinc oxide, unless your doctor has told you to.

There may be other drugs that can interact with zinc oxide topical or rectal suppositories. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Znlin resources

• Znlin Side Effects (in more detail)
• Znlin Use in Pregnancy & Breastfeeding
• Znlin Support Group
• 0 Reviews for Znlin - Add your own review/rating

• Arcalyst Monograph (AHFS DI)


• Caldesene Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• Desitin Cream MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Znlin with other medications

• Anal Itching
• Dermatologic Lesion

Where can I get more information?

• Your pharmacist can provide more information about zinc oxide topical.

See also: Znlin side effects (in more detail)

Hydromorphone Injection

Generic Name: hydromorphone hydrochloride

Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION

WARNING: RISK OF RESPIRATORY DEPRESSION AND ABUSE

Hydromorphone Hydrochloride Injection, USP, is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. Schedule II opioid agonists, including morphine, oxymorphone, hydromorphone, oxycodone, fentanyl and methadone, have the highest potential for abuse and risk of producing fatal overdose due to respiratory depression. Ethanol, other opioids, and other central nervous system depressants (e.g., sedative-hypnotics, skeletal muscle relaxants) can potentiate the respiratory-depressant effects of hydromorphone and increase the risk of adverse outcomes, including death. (5.1)

Hydromorphone can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing Hydromorphone in situations where the healthcare professional is concerned about increased risk of misuse or abuse. (5.2)

Indications and Usage for Hydromorphone Injection

Hydromorphone hydrochloride is indicated for the management of pain in patients where an opioid analgesic is appropriate.

Hydromorphone Injection Dosage and Administration

General Dosing Considerations

Selection of patients and administration of hydromorphone hydrochloride injection should be governed by the same principles that apply to the use of similar opioid analgesics to treat patients with acute or chronic pain, and depends upon a comprehensive assessment of the patient. Individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.

The nature of the pain, (severity, frequency, etiology, and pathophysiology) as well as the medical status of the patient, will affect selection of the starting dosage. Opioid analgesics, including hydromorphone hydrochloride injection, have a narrow therapeutic index in certain patient populations, especially when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks.

Individualization of Dosage

Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment. Give attention to the following:

• the age, general condition and medical status of the patient;


• the patient's degree of opioid tolerance;


• the daily dose, potency, and specific characteristics of the opioid the patient has been taking previously;


• concurrent medications;


• the type and severity of the patient’s pain;


• risk factors for abuse or addiction; including whether the patient has a previous or current substance abuse problem, a family history of substance abuse, or a history of mental illness or depression;


• the balance between pain control and adverse reactions

Periodic reassessment after the initial dosing of hydromorphone hydrochloride injection is required. If pain management is not satisfactory, and opioid-induced adverse events are tolerable, the hydromorphone dose may be increased gradually. If excessive opioid side effects are observed early in the dosing interval, reduce the hydromorphone hydrochloride dose. If this results in breakthrough pain at the end of the dosing interval, the dosing interval may need to be shortened. Dose titration should be guided more by the need for analgesia and the occurrence of adverse events than the absolute dose of opioid employed.

Subcutaneous or Intramuscular Administration

The usual starting dose is 1 mg to 2 mg subcutaneously or intramuscularly every 2 to 3 hours as necessary for pain. Depending on the clinical situation, the initial starting dose may be lowered in patients who are opioid naïve. Adjust the dose according to the severity of pain and occurrence of adverse events, as well as the patient's underlying disease and age.

 Intravenous Administration

The initial intravenous starting dose is 0.2 mg to 1 mg every 2 to 3 hours as necessary for pain control.

Administer intravenous hydromorphone slowly, over at least 2 to 3 minutes, depending on the dose. Titrate the dose to achieve acceptable pain management and tolerable adverse events. Reduce the initial dose in the elderly or debilitated.

Hepatic Impairment

Start patients with hepatic impairment on one-fourth to one-half the usual dose of hydromorphone hydrochloride injection depending on the extent of impairment [see Clinical Pharmacology, Pharmacokinetics and Metabolism (12.3)].

Renal Impairment

Start patients with renal impairment on one-fourth to one-half the usual starting dose of hydromorphone hydrochloride injection depending on the degree of impairment [see Clinical Pharmacology, Pharmacokinetics (12.3)].

Conversion from Prior Opioid

Use the equianalgesic dose table below (Table 1) as a guide to determine the appropriate dose of Hydromorphone Injection. Convert the current total daily amount(s) of opioid(s) received to an equivalent total daily dose of Hydromorphone Injection and reduce by one-half due to the possibility of incomplete cross tolerance. Divide the new total amount by number of doses permitted based on dosing interval (e.g. 8 doses for every-three-hour dosing). Titrate the dose according to the patient's response. For opioids not in Table 1, first estimate the daily amount of morphine that is equivalent to the current total daily amount of other opioid(s) received, then use Table 1 to find the approximate equivalent total daily dose of Hydromorphone Injection.

Table 1 OPIOID ANALGESIC EQUIVALENTS WITH APPROXIMATELY EQUIANALGESIC POTENCY FOR CONVERSION TO Hydromorphone Injection*

DRUG SUBSTANCE	PARENTERAL DOSE	ORAL DOSE
Morphine Sulfate	10 mg	40 – 60 mg
Hydromorphone HCl	1.3 – 2 mg	6.5 – 7.5 mg
Oxymorphone HCl	1 – 1.1 mg	6.6 mg
Levorphanol tartrate	2 – 2.3 mg	4 mg
Meperidine HCl (pethidine HCl)	75 – 100 mg	300 – 400 mg
Methadone HCl	10 mg	10 – 20 mg
Nalbuphine HCl	10 – 12 mg	–
Butorphanol tartrate	1.5 – 2.5 mg	–
* Dosages, and ranges of dosages represented, are a compilation of estimated equipotent dosages from published references comparing opioid analgesics in cancer and severe pain.

Administration

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A slight yellowish discoloration may develop in hydromorphone hydrochloride ampules. No loss of potency has been demonstrated. Hydromorphone hydrochloride is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.

Dosage Forms and Strengths

Hydromorphone hydrochloride injections are available as:

• Ampules                              1 mg/mL, 2 mg/mL, and 4 mg/mL


• Carpuject Syringes              1 mg/mL, 2 mg/mL, and 4 mg/mL


• iSecure Syringes                  0.5 mg/0.5 mL, 1 mg/mL, and 2 mg/mL


• Vials                                     2 mg/mL

The drug product is a clear, colorless to nearly colorless aqueous sterile solution. Each 1 mL of sterile solution contains 1 mg, 2 mg or 4 mg hydromorphone hydrochloride.

Contraindications

Hydromorphone hydrochloride is contraindicated:

• in patients with known hypersensitivity to hydromorphone


• in any situation where opioids are contraindicated, e.g., in patients with respiratory depression in the absence of resuscitative equipment or in unmonitored settings; or patients with acute or severe bronchial asthma


• in patients with, or at risk of developing, gastrointestinal obstruction, especially paralytic ileus because hydromorphone diminishes the propulsive peristaltic wave in the gastrointestinal tract and may prolong the obstruction.

Warnings and Precautions

Respiratory Depression

Respiratory depression is the chief hazard of hydromorphone hydrochloride. Respiratory depression occurs most frequently in the elderly, in the debilitated, and in those suffering from conditions accompanied by hypoxia or hypercapnia, or upper airway obstruction in whom even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Respiratory depression is also a particular problem following large initial doses in non opioid-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.

Use hydromorphone hydrochloride with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. In such patients, even usual therapeutic doses of opioid analgesics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative non-opioid analgesics should be considered, and hydromorphone hydrochloride should be employed only under careful medical supervision at the lowest effective dose in such patients.

Misuse and Abuse of Opioids

Hydromorphone is an opioid agonist with an abuse liability similar to morphine and a Schedule II, controlled substance. Hydromorphone has the potential for being abused, is sought by drug abusers and people with addiction disorders, and is subject to criminal diversion. Diversion of Schedule II products is an act subject to criminal penalty.

Abuse of hydromorphone hydrochloride poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol or other substances. Schedule II opioid agonists have the highest potential for abuse and risk of fatal respiratory depression.

Hydromorphone Injection can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Hydromorphone Injection in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Risk of Medication Errors

Hydromorphone for parenteral administration is marketed in several concentrations. Take precautions to ensure that the different concentrations are not confused to avoid the risk of accidental overdose and death.

Hydromorphone does not convert to morphine on a milligram per milligram basis. Use Table 1 when converting a patient from morphine to hydromorphone to avoid errors that can lead to overdose or death.

 Interactions with Alcohol, CNS Depressants, and Drugs of Abuse

The concurrent use of hydromorphone hydrochloride with other central nervous system (CNS) depressants, including but not limited to other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants.

 Neonatal Withdrawal Syndrome

Infants born to mothers physically dependent on hydromorphone hydrochloride injection will also be physically dependent and may exhibit signs of withdrawal. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. Neonatal opioid withdrawal syndrome may be life threatening and should be treated according to protocols developed by neonatology experts [see Drug Abuse and Dependence (9.3)].

 Use in Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of hydromorphone hydrochloride injection promote carbon dioxide retention which results in elevation of cerebrospinal fluid pressure. This increase in intracranial pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or other conditions that predispose to increased intracranial pressure.

Hydromorphone hydrochloride injection may produce effects on pupillary response and consciousness which can obscure the clinical course and neurologic signs of further increase in pressure in patients with head injuries.

 Hypotensive Effects

Hydromorphone hydrochloride, may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume, or a concurrent administration of drugs such as phenothiazines or general anesthetics [see Warnings and Precautions (5), Drug Interactions (7)]. Hydromorphone hydrochloride may product orthostatic hypotension in ambulatory patients.

Administer hydromorphone hydrochloride with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

 Use in Pancreatic/Biliary Tract Disease and Other Gastrointestinal Conditions

The administration of hydromorphone hydrochloride injection may obscure the diagnosis or clinical course in patients with acute abdominal conditions [see Contraindications (4)].

Use hydromorphone hydrochloride injection with caution in patients who are at risk of developing ileus.

Use hydromorphone hydrochloride injection with caution in patients with biliary tract disease, including acute pancreatitis, as hydromorphone may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions.

Special Risk Patients

Give hydromorphone hydrochloride with caution and the initial dose should be reduced in the elderly or debilitated and those with severe impairment of hepatic, pulmonary or renal function; myxedema or hypothyroidism; adrenocortical insufficiency (e.g., Addison’s Disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis associated with respiratory depression.

The administration of opioid analgesics including hydromorphone hydrochloride injection may aggravate preexisting convulsions in patients with convulsive disorders.

Hydromorphone, as with other opioids, may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings.

Reports of mild to severe seizures and myoclonus have been reported in severely compromised patients, administered high doses of parenteral hydromorphone.

Use in Drug and Alcohol Dependent Patients

Use hydromorphone hydrochloride with caution in patients with alcoholism and other drug dependencies due to the increased frequency of opioid tolerance, dependence, and the risk of addiction observed in these patient populations. Abuse of hydromorphone hydrochloride in combination with other CNS depressant drugs can result in serious risk to the patient.

Hydromorphone is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission is for the management of pain requiring opioid analgesia.

 Use in Ambulatory Patients

Hydromorphone hydrochloride may impair the mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients should be cautioned accordingly. Hydromorphone hydrochloride may produce orthostatic hypotension in ambulatory patients [see Drug Interactions (7)].

 Parenteral Administration

Hydromorphone hydrochloride injection may be given intravenously, but the injection should be given very slowly. Rapid intravenous injection of opioid analgesics increases the possibility of side effects such as hypotension and respiratory depression [see Dosage and Administration (2.3)].

Adverse Reactions

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 rates observed in practice.

Serious adverse reactions associated with hydromorphone hydrochloride include respiratory depression and apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest have occurred.

The following serious adverse reactions described elsewhere in the labeling include:

• Respiratory depression and secondary effects on intracranial pressure [see Warnings and Precautions (5.1, 5.6)].


• Hypotension [see Warnings and Precautions (5.7)].


• Gastrointestinal effects and effects in sphincter of Oddi [see Warnings and Precautions (5.8)].


• Drug abuse, addiction, and dependence [see Drug Abuse and Dependence (9.2, 9.3)].


• Effects on the ability to drive and operate machinery [see Warnings and Precautions (5.11)].

The most common adverse effects are light-headedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain.

Less Frequently Observed Adverse Reactions

Cardiac disorders: tachycardia, bradycardia, palpitations

Eye disorders: vision blurred, diplopia, miosis, visual impairment

Gastrointestinal disorders: constipation, ileus, diarrhea, abdominal pain

General disorders and administration site conditions: weakness, feeling abnormal, chills, injection site urticaria

Hepatobiliary disorders: biliary colic

Metabolism and nutrition disorders: decreased appetite

Musculoskeletal and connective tissue disorders: muscle rigidity

Nervous system disorders: headache, tremor, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncope

Psychiatric disorders: agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreams

Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects

Respiratory, thoracic and mediastinal disorders: bronchospasm, laryngospasm

Skin and subcutaneous tissue disorders: injection site pain, urticaria, rash, hyperhidrosis

Vascular disorders: flushing, hypotension, hypertension 

 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of hydromorphone. 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: anaphylactic reactions, confusional state, convulsions, dyskinesia, dyspnea, erectile dysfunction, hepatic enzyme increased, hyperalgesia, hypersensitivity reaction, injection site reactions, myoclonus, oropharyngeal swelling, peripheral edema, somnolence.

Drug Interactions

 Interactions with other CNS Depressants

Hydromorphone hydrochloride injection should be used with caution and in reduced dosages when administered to patients concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, centrally acting anti-emetics, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result.

When such combined therapy is contemplated, the dose of one or both agents should be reduced. Opioid analgesics, including hydromorphone hydrochloride, may enhance the action of neuromuscular blocking agents and produce an increased degree of respiratory depression.

 Interactions with Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as hydromorphone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of hydromorphone and/or may precipitate withdrawal symptoms in these patients.

 Monoamine Oxidase Inhibitors (MAOIs)

MAOIs may potentiate the action of hydromorphone hydrochloride. Allow at least 14 days after stopping treatment with MAOIs before initiating treatment with hydromorphone hydrochloride.

 Anticholinergics

Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics including hydromorphone hydrochloride injection may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. Hydromorphone hydrochloride injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

No effects on teratogenicity or embryotoxicity were observed in pregnant rats given oral doses up to 7 mg/kg/day which is 3-fold higher than the human dose of 24 mg hydromorphone hydrochloride injection (4 mg every 4 hours), on a body surface area basis. Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenic effects likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8-10), doses ≥ 19 mg/kg of hydromorphone produced skull malformations (exencephaly and cranioschisis). In CF-1 mice, continuous infusion of hydromorphone (> 15 mg/kg over 24 hours) via implanted osmotic pumps during organogenesis (gestation days 7-10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricles and retina), and skeletal variations (split supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were observed at doses approximately 6-fold and 3-fold higher, respectively, than the human dose of 24 mg hydromorphone hydrochloride (4 mg every 4 hours), on a body surface area basis.

Labor And Delivery

Hydromorphone hydrochloride should be used with caution during labor. Occasionally, opioid analgesics including hydromorphone hydrochloride injection may prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.

Opioid analgesics, including hydromorphone hydrochloride, may cause respiratory depression in the newborn. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. Have a specific opioid antagonist, such as naloxone or nalmefene, available for reversal of opioid-induced respiratory depression in the neonate.

Neonates whose mothers have been taking opioids chronically may also exhibit withdrawal signs, either at birth or in the nursery, because they have developed physical dependence. This is not, however, synonymous with addiction [see Drug Abuse and Dependence (9.3)]. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts [see Warnings and Precautions (5.5)].

The effect of hydromorphone hydrochloride, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers

Low levels of opioid analgesics have been detected in human milk. As a general rule, nursing should not be undertaken while a patient is receiving hydromorphone hydrochloride injection since it, and other drugs in this class, may be excreted in the milk.

Pediatric Use

The safety and effectiveness of hydromorphone hydrochloride injection in pediatric patients has not been established.

Geriatric Use

Clinical studies of hydromorphone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Respiratory depression is the chief risk in elderly or debilitated patients, usually the result of large initial doses in non-opioid-tolerant patients. Titration in these patients should proceed cautiously [see Individualization of Dosage (2.2) and Warnings and Precautions (5)].

Renal Impairment

The pharmacokinetics of hydromorphone following an oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets) are affected by renal impairment. Mean exposure to hydromorphone (Cmax and AUC0-∞) is increased by 2 fold in patients with moderate (CLcr = 40 - 60 mL/min) renal impairment and increased by 4 fold in patients with severe (CLcr < 30 mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min). In addition, in patients with severe renal impairment, hydromorphone appeared to be more slowly eliminated with a longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration. [see Clinical Pharmacology (12.3)]

Hepatic Impairment

The pharmacokinetics of hydromorphone following an oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets) are affected by hepatic impairment. Mean exposure to hydromorphone (Cmax and AUC∞) is increased 4 fold in patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal hepatic function. Due to increased exposure of hydromorphone, patients with moderate hepatic impairment should be started at one fourth to one half the recommended starting dose depending on the degree of hepatic dysfunction and closely monitored during dose titration. The pharmacokinetics of hydromorphone in patients with severe hepatic impairment has not been studied. A further increase in Cmax and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see Clinical Pharmacology (12.3)].

Drug Abuse and Dependence

Controlled Substance

Hydromorphone hydrochloride injection is a Schedule II controlled substance with an abuse liability similar to morphine. Hydromorphone hydrochloride can be abused and is subject to criminal diversion.

Abuse

Hydromorphone hydrochloride injection is intended for parenteral use only under the direct supervision of an appropriately licensed health care professional.

Abuse of hydromorphone hydrochloride injection poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol or other substances. Parenteral drug abuse is commonly associated with transmission of infectious diseases, such as hepatitis and HIV.

Hydromorphone hydrochloride injection can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing, dispensing, ordering, or administering hydromorphone hydrochloride injection in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Prescribers should monitor all patients receiving opioids for signs of abuse, misuse, and addiction. Furthermore, patients should be assessed for their potential for opioid abuse prior to being prescribed opioid therapy. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental illness (e.g., depression). Opioids may still be appropriate for use in these patients, however, they will require intensive monitoring for indications of abuse.

Opioid drugs are sought by people with substance use disorders (abuse or addiction, the latter of which is also called “substance dependence”) and criminals who supply them by diverting medicines out of legitimate distribution channels. Hydromorphone hydrochloride injection is a target for diversion.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include, but are not limited to, emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, altering or forging of prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among people with untreated substance use disorders, and criminals who divert controlled substances.

The risks of misuse and abuse should be considered when prescribing or dispensing hydromorphone hydrochloride injection. Concerns about abuse and addiction, should not prevent the proper management of pain, however. Treatment of pain should be individualized, balancing the potential benefits and risks for each patient.

Addiction is a chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, proper dispensing and correct storage and handling are appropriate measures that help to limit misuse and abuse of opioid drugs. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Dependence

Tolerance to opioids is demonstrated by the need for increasing doses to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance to different effects of opioids may develop to varying degrees and at varying rates in a given individual. There is also inter-patient variability in the rate and extent of tolerance that develops to various opioid effects, whether the effect is desirable (e.g., analgesia) or undesirable (e.g., nausea). In general, patients taking opioid analgesics that are appropriately titrated for pain control develop tolerance to the respiratory depressant effects fairly reliably. Conversely, tolerance to the constipating effects of opioids rarely develops, even when they are administered over long periods of time.

Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

In general, opioids used regularly should not be abruptly discontinued.

Overdosage

Signs and Symptoms

Signs and symptoms of acute overdosage with hydromorphone hydrochloride injection include: respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, apnea, circulatory collapse, cardiac arrest, and death.

Hydromorphone may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Treatment

In the treatment of overdosage, primary attention should be given to re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.

The opioid antagonists, naloxone, is a specific antidote against respiratory depression which may result from overdosage, or unusual sensitivity to hydromorphone hydrochloride. Therefore an appropriate dose of this antagonist should be administered preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression. Naloxone should be administered cautiously to persons who are known, or suspected to be physically dependent on hydromorphone hydrochloride. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Since the duration of action of hydromorphone hydrochloride may exceed that of the antagonist, the patient should be kept under continued surveillance; repeated doses of the antagonist may be required to maintain adequate respiration. Apply other supportive measures when indicated.

Hydromorphone Injection Description

Hydromorphone hydrochloride, a hydrogenated ketone of morphine, is an opioid analgesic. The chemical name of hydromorphone hydrochloride is 4,5α- epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride.

The structural formula is:

The drug product is an aqueous sterile solution. Each 1 mL of sterile solution contains 1 mg, 2 mg, or 4 mg hydromorphone hydrochloride for the respective product strength.  Each 1 mL also contains 5.4 mg sodium lactate and sodium chloride for isotonicity. The solution pH is adjusted with lactic acid or sodium hydroxide to between pH 3.5 and 5.5.

Hydromorphone Injection - Clinical Pharmacology

Mechanism of Action

The precise mode of analgesic action of opioid analgesics is unknown. However, specific CNS opiate receptors have been identified. Opioids are believed to express their pharmacological effects by combining with these receptors.

Hydromorphone hydrochloride is a mu-opioid receptor agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, fentanyl, codeine, hydrocodone and oxymorphone.

Central Nervous System

Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, and cough suppression, as well as analgesia.

Hydromorphone produces respiratory depression by direct effect on brain stem respiratory centers. The mechanism of respiratory depression also involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension.

Hydromorphone causes miosis. Pinpoint pupils are a common sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).

Gastrointestinal Tract and Other Smooth Muscle

Gastric, biliary and pancreatic secretions are decreased by opioids such as hydromorphone. Hydromorphone causes a reduction in motility associated with an increase in tone in the gastric antrum and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, and tone may be increased to the point of spasm. The end result is constipation. Hydromorphone can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.

Cardiovascular System 

Hydromorphone may produce hypotension as a result of either peripheral vasodilation, release of histamine, or both. Other manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, and red eyes.

Effects on the myocardium after intravenous administration of opioids are not significant in normal persons, vary with different opioid analgesic agents and vary with the hemodynamic state of the patient, state of hydration and sympathetic drive.

Immune System

In vitro and animal studies indicate that opioids have a variety of effects on immune functions. The clinical significance of these findings is unknown.

Pharmacokinetics

Distribution

At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma proteins. After an intravenous bolus dose, the steady state of volume of distribution [mean (%cv)] is 302.9 (32%) liters.

Metabolism

Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites.

Elimination

Only a small amount of the hydromorphone dose is excreted unchanged in the urine. Most of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites. The systemic clearance is approximately 1.96 (20%) liters/minute. The terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours.

Special Populations

Hepatic Impairment 

After oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets), mean exposure to hydromorphone (Cmax and AUC∞) is increased 4 fold in patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal hepatic function. Patients with moderate hepatic impairment should be started at one fourth to one half the recommended starting dose and closely monitored during dose titration. The pharmacokinetics of hydromorphone in patients with severe hepatic impairment has not been studied. A further increase in Cmax and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see Use in Specific Populations (8.7)].

Renal Impairment 

The pharmacokinetics of hydromorphone following an oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets) are affected by renal impairment. Mean exposure to hydromorphone (Cmax and AUC0-∞) is increased by 2 fold in patients with moderate (CLcr = 40 - 60 mL/min) renal impairment and increased by 4 fold in patients with severe (CLcr < 30 mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min). In addition, in patients with severe renal impairment, hydromorphone appeared to be more slowly eliminated with a longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration [see Use in Specific Populations (8.6)].

Pediatrics 

Pharmacokinetics of hydromorphone have not been evaluated in children.

Geriatric 

In the geriatric population, age has no effect on the pharmacokinetics of hydromorphone.

Gender 

Gender has little effect on the pharmacokinetics of hydromorphone. Females appear to have a higher Cmax (25%) than males with comparable AUC0-24 values. The difference observed in Cmax may not be clinically relevant.

Race

The effect of race on hydromorphone pharmacokinetics has not been studied.

Pregnancy and Nursing Mothers

Hydromorphone crosses the placenta. Hydromorphone is also found in low levels in breast milk, and may cause respiratory compromise in newborns when administered during labor or delivery.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long term studies in animals to evaluate the carcinogenic potential of hydromorphone have not been conducted.

Mutagenesis

Hydromorphone was not mutagenic in the in vitro bacterial reverse m