Estring local

Generic Name: estradiol vaginal (local) (ess tra DYE ole VAJ in ul (LO kul))

Brand Names: Estrace Vaginal, Estring, Vagifem

What is estradiol vaginal (local)?

Estradiol is a form of estrogen, a female sex hormone the regulates many processes in the body.

Estradiol vaginal (local) is used to treat certain symptoms of menopause such as dryness, burning, and itching of the vaginal area. Estradiol vaginal also reduces urgency or irritation of urination.

Estradiol vaginal (local) may also be used for purposes not listed in this medication guide.

What is the most important information I should know about estradiol vaginal (local)?

Some estradiol products placed directly into the vagina are used for "local" treatment of vaginal menopause symptoms involving the secretions and surrounding tissues of the vagina. Other vaginal estradiol products are used for treating menopause symptoms affecting the vagina as well as other parts of the body (such as hot flashes). This type of vaginal estradiol has "systemic" effects, meaning that it can affect parts of the body other than where the medicine is placed or applied.

The information in this leaflet is specific to estradiol vaginal products that are used for local treatment of symptoms.

Do not use this medication if you have any of the following conditions: a history of stroke or blood clot, circulation problems, a hormone-related cancer such as breast or uterine cancer, or abnormal vaginal bleeding. This medication can cause birth defects in an unborn baby. Do not use if you are pregnant. Use an effective form of birth control, and tell your doctor if you become pregnant during treatment.

Estradiol increases your risk of developing endometrial hyperplasia, a condition that may lead to cancer of the uterus. Taking progestins while using estradiol may lower this risk. If your uterus has not been removed, your doctor may prescribe a progestin for you to take while you are using estradiol vaginal.

Long-term estradiol treatment may increase your risk of breast cancer, heart attack, or stroke. Talk with your doctor about your individual risks before using estradiol long-term. Your doctor should check your progress on a regular basis (every 3 to 6 months) to determine whether you should continue this treatment.

Have regular physical exams and self-examine your breasts for lumps on a monthly basis while using estradiol.

What should I discuss with my healthcare provider before using estradiol vaginal (local)?

You should not use estradiol vaginal if you have:

• 
  

  a bleeding or blood-clotting disorder;

  
  


• 
  

  a history of stroke or circulation problems;

  
  


• 
  

  abnormal vaginal bleeding that a doctor has not checked; or

  
  


• 
  

  any type of breast, uterine, or hormone-dependent cancer.

  
  

To make sure you can safely use estradiol vaginal, tell your doctor if you have any of these other conditions:

• 
  

  high blood pressure, angina, or heart disease;

  
  


• 
  

  high cholesterol or triglycerides;

  
  


• liver disease;


• kidney disease;


• 
  

  asthma;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  migraines;

  
  


• 
  

  diabetes;

  
  


• 
  

  depression;

  
  


• 
  

  gallbladder disease; or

  
  


• 
  

  if you have had your uterus removed (hysterectomy).

  
  

Estradiol increases your risk of developing endometrial hyperplasia, a condition that may lead to cancer of the uterus. Taking progestins while using estradiol may lower this risk. If your uterus has not been removed, your doctor may prescribe a progestin for you to take while you are using estradiol vaginal.

FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not use estradiol vaginal if you are pregnant. Tell your doctor right away if you become pregnant during treatment.

Long-term estradiol treatment may increase your risk of stroke. Talk with your doctor about your individual risks before using estradiol long-term. Your doctor should check your progress on a regular basis (every 3 to 6 months) to determine whether you should continue this treatment.

Estradiol may decrease breast milk flow and have other effects on milk composition. Do not use estradiol without first talking to your doctor if you are breast-feeding a baby.

How should I use estradiol vaginal (local)?

Some estradiol products placed directly into the vagina are used for "local" treatment of vaginal menopause symptoms involving the secretions and surrounding tissues of the vagina. Other vaginal estradiol products are used for treating menopause symptoms affecting the vagina as well as other parts of the body (such as hot flashes). This type of vaginal estradiol has "systemic" effects, meaning that it can affect parts of the body other than where the medicine is placed or applied.

The information in this leaflet is specific to estradiol vaginal products that are used for local treatment of symptoms.

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

To use the estradiol vaginal ring:

• 
  

  Squeeze the sides of the ring together and insert it into the vagina as far as possible. You should not be able to feel the ring once it is in place. If you can feel it, use a finger to push it in farther. It is not possible for the ring to go too far in or become lost.

  
  


• 
  

  Leave the ring in place for 90 days. If the ring ever falls out, rinse it with warm water and reinsert it. If it slides down into the lower part of the vagina, use a finger to push it in farther. After 90 days, remove the ring. Your doctor may want you to replace it with a new ring.

  
  


• 
  

  The ring does not need to be removed during sexual intercourse. Neither partner should be able to feel the ring when it is in place. If the ring is bothersome, you may remove it, rinse it with warm water, and reinsert it after intercourse.

  
  


• 
  

  To remove the ring, loop a finger through the ring and gently pull it from the vagina.

  
  

To use the estradiol vaginal cream:

• 
  

  Using the marked applicator provided, measure the prescribed dose of cream.

  
  


• 
  

  Lie on your back with your knees drawn up, sit, or stand in a position that allows you comfortable access to the vaginal area. Gently insert the applicator deep into your vagina and press in the plunger to empty the cream from the applicator into the vagina.

  
  


• 
  

  Take apart the applicator and wash it with mild soap and warm water. Allow the applicator to dry completely before using it again.

  
  

To use the estradiol vaginal tablets:

• 
  

  Each vaginal tablet is supplied in a disposable applicator.

  
  


• 
  

  Lie on your back with your knees drawn up, sit, or stand in a position that allows you comfortable access to the vaginal area. Gently insert the applicator deep into your vagina and press in the plunger to empty the tablet into the vagina.

  
  


• 
  

  Throw the applicator away.

  
  

Have regular physical exams and self-examine your breasts for lumps on a monthly basis while using estradiol vaginal.

Store this medication at room temperature away from moisture and heat.

What happens if I miss a dose?

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

If a vaginal ring falls out, rinse it with warm water and reinsert it. If it slides down into the lower part of the vagina, use a finger to push it in farther.

What happens if I overdose?

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

Overdose symptoms may include nausea, vomiting, and vaginal bleeding.

What should I avoid while using estradiol vaginal (local)?

Avoid using other vaginal products without your doctor's advice.

Estradiol vaginal (local) side effects

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

• 
  

  chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

  
  


• 
  

  sudden numbness or weakness, especially on one side of the body;

  
  


• 
  

  sudden headache, confusion, problems with vision, speech, or balance;

  
  


• 
  

  pain, swelling, warmth, or redness in one or both legs;

  
  


• 
  

  abnormal vaginal bleeding;

  
  


• 
  

  pain, swelling, or tenderness in your stomach;

  
  


• 
  

  jaundice (yellowing of the skin or eyes); or

  
  


• 
  

  a lump in your breast.

  
  

Less serious side effects may include:

• 
  

  nausea, vomiting, loss of appetite;

  
  


• 
  

  swollen breasts;

  
  


• 
  

  acne or skin color changes;

  
  


• 
  

  decreased sex drive, impotence, or difficulty having an orgasm;

  
  


• 
  

  migraine headaches or dizziness;

  
  


• 
  

  vaginal pain, dryness, or discomfort;

  
  


• 
  

  swelling of your ankles or feet;

  
  


• 
  

  depression; or

  
  


• 
  

  changes in your menstrual periods, break-through bleeding.

  
  

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 estradiol vaginal (local)?

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

• 
  

  St. John's wort;

  
  


• 
  

  phenobarbital (Solfoton);

  
  


• 
  

  a blood thinner such as warfarin (Coumadin, Jantoven);

  
  


• 
  

  ritonavir (Norvir, Kaletra);

  
  


• 
  

  carbamazepine (Carbatrol, Tegretol);

  
  


• 
  

  rifampin (Rifadin, Rifater, Rifamate, Rimactane);

  
  


• 
  

  antibiotics such as clarithromycin (Biaxin) or erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole); or

  
  


• 
  

  antifungal medicine such as antifungal medication such as itraconazole (Sporanox), ketoconazole (Nizoral), miconazole (Oravig), or voriconazole (Vfend).

  
  

This list is not complete and other drugs may interact with estradiol vaginal. 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 Estring resources

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

Compare Estring with other medications

• Atrophic Urethritis
• Atrophic Vaginitis
• Hypoestrogenism

Where can I get more information?

• Your pharmacist can provide more information about estradiol vaginal (local).

See also: Estring side effects (in more detail)

Fludara

Generic Name: Fludarabine Phosphate
Class: Antineoplastic Agents
VA Class: AN300
Chemical Name: 2-Fluoro-9-(5-O-phosphono-β-D-arabinofuranosyl)9H -purin-6-amine
Molecular Formula: C₁₀H₁₃FN₅O₇P
CAS Number: 75607-67-9

• Myelosuppression


• 
  

  Risk of severe bone marrow suppression.^{1 2 3 4 5 6 22 23 39 95} (See Hematologic Effects under Cautions.)

  
  

• Hemolysis


• 
  

  Possible life-threatening and sometimes fatal autoimmune hemolytic anemia after one or more courses of fludarabine therapy.¹ Evaluate and monitor patients closely for hemolysis.^{1 95} (See Hematologic Effects under Cautions.)

  
  

• Neurotoxicity


• 
  

  Possible severe neurologic effects (e.g., blindness, coma, death) following administration of high dosages (96 mg/m²; approximately 4 times the currently recommended dosage for chronic lymphocytic leukemia [CLL]) to patients with acute leukemia.^{1 2 3 5 6 9 29 30 31 45 95} Risk of CNS effects in patients receiving relatively low dosages (e.g., equivalent to those currently recommended for CLL).^{1 3 5 6 9 30 39 45 52 95} (See Neurotoxicity under Cautions.)

  
  
  • Pulmonary Toxicity
  
  
  • 
    

    Possible fatal pulmonary toxicity associated with concomitant use of fludarabine and pentostatin.^{1 8 87} Do not use fludarabine concomitantly with pentostatin.^{1 8 87 95} (See Specific Drugs under Interactions.)

    
    
  
  
  • Experience of Supervising Clinician
  
  
  • 
    

    Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.^{1 9 95}

    
    
  
  

Introduction

Antimetabolite antineoplastic agent; synthetic purine antagonist.^{1 2 3 4 5 6 7 9 21 95}

Uses for Fludara

Chronic Lymphocytic Leukemia (CLL)

Treatment of B-cell CLL (B-CLL) in patients refractory to at least one standard alkylating agent-containing regimen (e.g., chlorambucil with or without prednisone) or whose disease has progressed during treatment;^{1 2 3 4 6 14 15 20 21 44 58 64} considered a drug of choice.^{92 95} Has been designated an orphan drug by FDA for this use.²⁵

Used in the management of previously untreated† CLL^{2 3 4 6 14 46 58 59} (has been designated an orphan drug by FDA for this use)²⁵ or in leukemia that was contemporaneously responsive to standard therapy†.^{1 2 4 6 14 24 46 58 59}

Non-Hodgkin’s Lymphoma

Treatment of low-grade, advanced (stage III or IV) adult non-Hodgkin’s lymphoma† that failed or relapsed after previous therapy†;^{2 6 15 23 39 40 41 62 63 92} has been designated an orphan drug by FDA for use in this condition.²⁵

Acute Leukemias

Treatment of either acute myeloid (myelogenous, nonlymphocytic) leukemia† (AML, ANLL) or acute lymphocytic leukemia† (ALL) refractory to conventional therapy or which has relapsed following remission.^{2 5 29 30 31 45 92}

Severe toxicity, associated with the relatively high dosages that appear to be necessary for adequate response in these leukemias, may preclude use of the drug as monotherapy for remission induction of these cancers.^{2 5 29 30 31 45 80 87 92}

Prolymphocytic Leukemia and Prolymphocytoid Variant

Palliative treatment of prolymphocytic leukemia† (PLL) or prolymphocytoid chronic lymphocytic leukemia† (CLL-Pro) refractory to standard chemotherapy (e.g., chlorambucil and prednisone).^{34 35 36 37 38 42}

Hairy Cell Leukemia

Treatment of hairy cell leukemia† (leukemic reticuloendotheliosis); other drugs (e.g., cladribine, pentostatin) considered the initial therapies of choice.^{28 64 88 89 90 91 92 93 94}

Waldenstrom’s Macroglobulinemia

Treatment of refractory macroglobulinemia†.^{6 21}

Mycosis Fungoides

Treatment of mycosis fungoides, a form of cutaneous T-cell lymphoma†.^{52 92}

Fludara Dosage and Administration

General

• 
  

  Risk of certain toxic effects (e.g., neurotoxicity) is increased with increasing dosage.^{1 2 3 4 5 6 9 29 30 31 45}

  
  


• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.^{1 95}

  
  

Administration

IV Administration

Administer by IV infusion.^{1 2 4 5 6 9 15 20 21 22 23 29 31 33 36 59 65 95}

Has been administered by rapid IV injection† and by continuous† IV infusion (e.g., over 48 hours).^{2 4 5 6 15 30 41 43 62 65}

Handle with caution (by trained nonpregnant personnel); use protective equipment (e.g., latex gloves, protective eyewear).¹ Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.^{1 95} If powder or solution of the drug comes in contact with the skin or mucosa, immediately wash affected area thoroughly with soap and water; flush affected eye(s) thoroughly with water¹ or saline.⁸⁰

Reconstitution

Reconstitute vial containing 50 mg of fludarabine phosphate powder by adding 2 mL of sterile water for injection to provide a solution containing 25 mg/mL.¹

Agitate the solution for complete dissolution of the drug in ≤15 seconds.⁸⁰

Dilution

Using the commercially available (25 mg/mL) or reconstituted solution, withdraw the appropriate dose and add to a compatible IV fluid (e.g., 100 or 125 mL of 5% dextrose or 0.9% sodium chloride injection).^{1 95}

Rate of Administration

Administer by IV infusion over 30 minutes.^{1 9 80 95}

It is not known whether the rate of IV administration affects the risk of toxicity; neurotoxicity has occurred with rapid IV injection or slow IV infusion.^{30 80 87}

Dosage

Available as fludarabine phosphate; dosage expressed in terms of the salt.^{1 9 95}

Pediatric Patients

Other Neoplasms†

Acute Lymphocytic Leukemia (ALL)†

IV

10.5 mg/m² as a loading dose followed by 30.5 mg/m² as a continuous infusion daily for 5 days tested in pediatric patients.^{1 95}

Solid Tumors

IV

Maximum tolerated dose was 7 mg/m² as a loading dose followed by 20 mg/m² as a continuous infusion daily for 5 days.^{1 95}

Adults

Chronic Lymphocytic Leukemia (CLL)

IV

Initially, 25 mg/m² administered as a single daily dose for 5 consecutive days;^{1 3 6 68 80 87} dosages up to 30 mg/m² have been administered as a single daily dose for 5 consecutive days.^{3 4 6 58 87 95}

Administer each 5-day course of therapy at 28-day intervals.^{1 3 6} Initially may administer for at least 2 or 3 courses to determine patient response, unless unacceptable toxicity or disease progression occurs.^{3 80 87} Continue therapy until a maximal response achieved or dose-limiting toxicity develops; if maximal response achieved without such toxicity, administer 3 additional courses of therapy and then discontinue the drug.^{1 3 95}

Decrease dosage or temporarily withhold therapy if evidence of hematologic or nonhematologic toxicity occurs;¹ delay or permanently discontinue drug if neurologic toxicity develops.¹ (See Neurotoxicity under Cautions.)

Some patients have received up to 15 courses of therapy.^{1 3 95}

Adjust dosage in patients who may be predisposed to fludarabine-induced toxicity (e.g., those with advanced age and/or impaired renal or bone marrow function).^{1 41}

Other Neoplasms†

IV

Administer 18–30 mg/m² daily for 5 consecutive days at 28-day intervals.^{2 6 21 22 23 32 33 36 38 41 52}

Prescribing Limits

Pediatric Patients

Other Neoplasms†

Solid Tumors†

IV

Maximum 7 mg/m² (as a loading dose) followed by 20 mg/m² once daily for 5 days.¹

Adults

Chronic Lymphocytic Leukemia (CLL)

IV

Maximum 40 mg/m² daily for 5 days may be well tolerated,²⁹ but the relative risk to benefit of dosages exceeding those currently recommended remains to be established; such dosages currently are not recommended except under controlled clinical conditions (e.g., in investigational protocols).^{80 87}

Special Populations

Renal Impairment

Decrease dosage by 20% in patients with moderate renal impairment (Cl_cr 30–70 mL/minute); not recommended in patients with severe renal impairment (Cl_cr <30 mL/minute).^{1 95}

Geriatric Patients

Possible age-related decreases in renal function; adjust dosage accordingly.^{1 95}

Consider substantial dosage reduction in patients with advanced Rai stage CLL.⁴

Cautions for Fludara

Contraindications

• 
  

  Known hypersensitivity to fludarabine and/or any ingredient in the formulation.^{1 95}

  
  

Warnings/Precautions

Warnings

Neurotoxicity

Severe, potentially irreversible or fatal neurologic effects (e.g., delayed, progressive encephalopathy and blindness, coma) reported;^{1 2 3 5 6 9 29 30 31 45 95} manifestations usually appear 21–60 days after completion of a course of therapy.^{1 2 29 30 31 95}

Neurotoxicity appears to be dose related:^{1 2 3 6 9 29 30 31 45 95} usually occurring with dosages higher than those currently recommended for CLL.^{1 2 3 5 6 9 29 30 31 41 45} However, such toxicity may occur rarely at relatively low dosages.^{1 3 5 9 30 45 52 95}

Monitoring for visual changes as evidence of neurotoxicity has been suggested.³⁰

Hematologic Effects

Risk of severe, cumulative, often reversible, myelosuppression (e.g., anemia, thrombocytopenia, neutropenia).^{1 2 3 4 5 6 9 22 23 39 95 95}

Dosage adjustment and interruption of therapy and/or transfusions may be needed depending on severity of myelosuppression.⁹ Recovery of neutrophil and platelet count usually is complete within 5–7 weeks after discontinuance of therapy, but occasionally may require longer periods.⁸⁷

Risk of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes fatal.^{1 95} Clinically significant cytopenia may last 2–12 months.^{1 95}

Risk of life-threatening and sometimes fatal autoimmune hemolytic anemia, may recur upon rechallenge; close monitoring for hemolysis recommended.^{1 95} Not known whether corticosteroids are beneficial for management of these hemolytic episodes.^{1 95}

Transfusion-associated Graft-versus-host Disease

Possible transfusion-associated graft-versus-host disease following transfusion of nonirradiated blood products.^{1 95} Consider use of irradiated blood products in patients requiring blood transfusions.^{1 95}

Pulmonary Toxicity

Risk of severe and/or fatal pulmonary toxicity (e.g., pneumonitis) when administered concomitantly with pentostatin; do not use fludarabine with pentostatin.^{1 8 87 95} (See Specific Drugs under Interactions.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm (skeletal malformations, external deformities); avoid pregnancy during therapy.^{1 95}

Use during pregnancy only in life-threatening situations or severe disease when safer drugs cannot be used or are ineffective.^{80 87}

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.^{1 95}

Sensitivity Reactions

Pulmonary Hypersensitivity

Possible pulmonary hypersensitivity (diffuse interstitial pneumonitis characterized by dyspnea, hypoxia, cough, and pulmonary infiltrates).^{1 3 5 6 9 35 60 51 95}

Interstitial pneumonitis usually delayed, occurring 3–28 days after administration of the third or later course of therapy.^{2 5 6 35 50}

General Precautions

Toxicity and Adequate Patient Monitoring

Highly toxic, very low therapeutic index; therapeutic response is unlikely without some evidence of toxicity.^{1 3 4 5 6 9 29 30 31 41 45} (See Boxed Warning.) Severe toxicity most likely in poor risk patients (e.g., geriatric patients, those with impaired renal or bone marrow function), but fatality may occur in those in relatively good condition.

Administer only under supervision of a qualified clinician experienced in the use of cytotoxic therapy.^{1 9 95}

Closely observe for signs of hematologic and nonhematologic toxicity during therapy.^{1 30 65 95}

If severe adverse effects occur, discontinue therapy or reduce dosage and institute appropriate measures as necessary.^{1 9 65 87 95}

Tumor Lysis Syndrome

May occur as a result of CLL treatment.^{1 3 6 9 53 65 95}

Increased risk in patients with large initial tumor burden.^{1 95}

Closely monitor such patients and take appropriate precautions.^{1 95} Consider potential benefit of prophylactic allopurinol, adequate hydration, and/or urinary alkalinization.^{53 65 80 87}

Specific Populations

Pregnancy

Category D.

Lactation

Not known whether fludarabine is distributed into milk.^{1 95} Discontinue nursing or the drug.^{1 95}

Pediatric Use

Safety and efficacy not established.^{1 80 87 95}

In clinical studies in a limited number of pediatric patients with certain cancers (e.g., acute leukemia, solid tumors),^{2 5 43} adverse effect profile generally was similar to that in adults.^{5 43 87}

Bone marrow suppression (particularly thrombocytopenia), fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection were reported.^{1 95} Pulmonary hypersensitivity and peripheral neuropathy not reported.^{1 95}

Geriatric Use

Safety and efficacy in geriatric patients have not been studied specifically to date; however, CLL, for which safety and efficacy have been established,^{1 2 3 4 6 9 14 15 20 21 58} occurs principally in patients >50 years of age.^{24 58 61}

Possible increased risk of fludarabine-induced toxicity due to age-related decrease in renal function.^{1 26 95} Closely monitor such patients (especially those with advanced Rai stage CLL)⁴ and adjust dosage accordingly.^{1 95}

Renal Impairment

Clearance of fludarabine directly correlates with creatinine clearance.^{1 41 80 87 95}

Possible increased risk of fludarabine-induced toxicity;^{1 2 3 95} monitor closely for excessive toxicity.^{1 95}

Adjust dosage carefully in patients with impaired renal function;^{1 41 80 87 95} reduce dosage in those with moderate renal impairment.^{1 95} Do not use fludarabine in patients with severe renal impairment.^{1 95} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea and/or vomiting,^{1 2 3 4 6 9 22 23 95} anorexia,^{1 9 95} diarrhea,^{1 3 4 6 22 95} GI bleeding,^{1 9 95} fever,^{1 3 4 22 95} chills,^{1 95} rash,^{1 2 3 4 6 9 22 95} urinary tract infection,^{1 9 95} edema,^{1 3 9 95} cough,^{1 4 95} dyspnea,^{1 4 95} upper respiratory infection,^{1 9 95} infection,^{1 3 4 22 38 95} weakness,^{1 3 9 95} pain,^{1 9 95} malaise,^{1 9 22 95} fatigue,^{1 9 22 95} paresthesia,^{1 3 9 95} visual disturbances.^{19 23 39}

Interactions for Fludara

Specific Drugs

Drug	Interaction	Comments
Corticosteroids (prednisone)	Increased incidence of opportunistic infections 44	Prednisone should be omitted from regimens containing fludarabine or other purine antagonists44
Cytarabine	Cytarabine substantially decreases fludarabine metabolism7 67 74 and may inhibit the antineoplastic effect of fludarabine 67
Pentostatin	Possible severe and/or fatal pulmonary toxicity (e.g., pneumonitis)1 8 87	Concomitant therapy is not recommended1 8 87

Fludara Pharmacokinetics

Pharmacokinetic parameters generally are expressed in terms of fludarabine (2-fluoro-ara-A) and fludarabine triphosphate (2-fluoro-ara-ATP).^{80 81}

Distribution

Extent

Widely distributed,^{2 9 69 80} with highest concentrations in the liver, kidneys, and spleen.^{2 9 70 85}

Extent of distribution into CNS in humans is not known.^{2 3 5 6 9 29 30 31 45}

Apparently crosses the placenta.^{1 95} Not known whether fludarabine is distributed into human milk.^{1 95}

Plasma Protein Binding

Approximately 19–29%.^{1 95}

Special Populations

AUC is similar in patients with moderate renal impairment (Cl_cr 17–41 mL/minute per 1.73 m²) to those with normal renal function.^{1 95}

Elimination

Metabolism

Fludarabine monophosphate is rapidly and completely dephosphorylated to fludarabine (2-fluoro-ara-A; an active metabolite) and then phosphorylated intracellularly via deoxycytidine kinase to fludarabine triphosphate (2-fluoro-ara-ATP; an active metabolite).^{1 2 3 4 5 6 7 62 66 67 68 69 70 75 76 77 78 79 95}

Elimination Route

Excreted principally in urine as fludarabine (2-fluoro-ara-A).^{1 41 95}

Half-life

Terminal half-life is about 20 hours.^{1 95}

Special Populations

Total body clearance is 124 and 172 mL/minute in patients with moderate renal impairment (Cl_cr 17–41 mL/minute per 1.73 m²) and in those with normal renal function, respectively.^{1 95}

Stability

Storage

Parenteral

Powder for Injection

2–8°C.¹ Do not store at room temperature.⁸⁰

Use reconstituted and diluted solutions within 8 hours after preparation.^{1 11 80}

Injection

2–8°C.⁹⁵

Discard unused solution within 8 hours after initial entry into vial.^{95 80}

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Drug Compatibility

Y-Site CompatibilityHID

Compatible
Allopurinol sodium
Amifostine
Amikacin sulfate
Aminophylline
Ampicillin sodium
Ampicillin sodium–sulbactam sodium
Amsacrine
Aztreonam
Bleomycin sulfate
Butorphanol tartrate
Carboplatin
Carmustine
Cefazolin sodium
Cefepime HCl
Cefotaxime sodium
Ceftazidime
Ceftizoxime sodium
Ceftriaxone sodium
Cefuroxime sodium
Cimetidine HCl
Cisplatin
Clindamycin phosphate
Co-trimoxazole
Cyclophosphamide
Cytarabine
Dacarbazine
Dactinomycin
Dexamethasone sodium phosphate
Diphenhydramine HCl
Doxorubicin HCl
Doxycycline hyclate
Droperidol
Etoposide
Etoposide phosphate
Famotidine
Filgrastim
Floxuridine
Fluconazole
Fluorouracil
Furosemide
Gemcitabine HCl
Gentamicin sulfate
Granisetron HCl
Haloperidol lactate
Heparin sodium
Hydrocortisone sodium phosphate
Hydrocortisone sodium succinate
Hydromorphone HCl
Ifosfamide
Imipenem–cilastatin sodium
Lorazepam
Magnesium sulfate
Mannitol
Melphalan HCl
Meperidine HCl
Mesna
Methotrexate sodium
Methylprednisolone sodium succinate
Metoclopramide HCl
Minocycline HCl
Mitoxantrone HCl
Morphine sulfate
Multivitamins
Nalbuphine HCl
Ondansetron HCl
Pentostatin
Piperacillin sodium–tazobactam sodium
Potassium chloride
Promethazine HCl
Ranitidine HCl
Sodium bicarbonate
Teniposide
Thiotepa
Ticarcillin disodium–clavulanate potassium
Tobramycin sulfate
Vancomycin HCl
Vinblastine sulfate
Vincristine sulfate
Vinorelbine tartrate
Zidovudine
Incompatible
Acyclovir sodium
Amphotericin B
Chlorpromazine HCl
Daunorubicin HCl
Ganciclovir sodium
Hydroxyzine HCl
Prochlorperazine edisylate

ActionsActions

• 
  

  Exact mechanism(s) not fully elucidated, but appears to involve inhibition of α-DNA polymerase, ribonucleotide reductase, and DNA primase through competition with the physiologic substrate, deoxyadenosine triphosphate, resulting in inhibition of DNA synthesis.^{1 2 3 4 5 6 7 95}

  
  


• 
  

  T cells are more sensitive than B cells to fludarabine's cytotoxic effects;^{2 4} drug is highly active against B-cell lymphoproliferative disorders, including CLL.^{1 2 3 4 6 9 14 15 20 21 58 64} Cytolytic effect appears to be relatively rapid even in neoplasms that are characterized by a slow proliferative rate.^{9 53}

  
  

Advice to Patients

• 
  

  Importance of immediately informing clinician if fever, sore throat, or unusual bleeding or bruising occurs.^{80 87}

  
  


• 
  

  Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy, advise pregnant women of risk to the fetus.^{1 95} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  
  


• 
  

  Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^{1 95}

  
  


• 
  

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

  
  

Preparations

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

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

Fludarabine Phosphate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV use only	50 mg	Fludara (with mannitol 50 mg)	Berlex
	Injection, for IV use only	25 mg/mL*	Fludarabine Phosphate Injection (preservative-free; with mannitol 25 mg/mL)	Sicor

Disclaimer

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

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

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

1. Berlex Laboratories. Fludara (fludarabine phosphate) for injection prescribing information. Montville, NJ: 2003 Oct.

2. Hood MA, Finley RS. Fludarabine: a review. DICP. 1991; 25:518-24. [IDIS 280755] [PubMed 2068837]

3. Anon. Fludarabine. Med Lett Drugs Ther. 1991; 33:89-90. (IDIS 285668)

4. Keating MJ. Fludarabine phosphate in the treatment of chronic lymphocytic leukemia. Semin Oncol. 1990; 17(Suppl 8):49-62. [PubMed 1699283]

5. Von Hoff DD. Phase I clinical trials with fludarabine phosphate. Semin Oncol. 1990; 17(Suppl 8):33-8. [PubMed 1699281]

6. Chun HG, Leyland-Jones B, Cheson BD. Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. J Clin Oncol. 1991; 9:175-88. [PubMed 1702143]

Boots Maximum Strength Cold & Flu Relief Direct Dose Lemon

1. Name Of The Medicinal Product

Boots Maximum Strength Cold & Flu Relief Direct Dose Lemon

2. Qualitative And Quantitative Composition

Active ingredients	mg/sachet
Paracetamol	1000.0
Phenylephrine hydrochloride	* 12.2

*This is equivalent to 10mg phenylephrine base.

For excipients, see 6.1.

3. Pharmaceutical Form

Oral powder

A white to off-white unit-dose powder with the odour and flavour of lemons.

4. Clinical Particulars

4.1 Therapeutic Indications

For relief of symptoms associated with the common cold and influenza, including the relief of aches and pains, sore throat, headache, nasal congestion and lowering of temperature.

4.2 Posology And Method Of Administration

Oral administration.

Adults and children 12 and over: One single-dose container. The product is taken orally without water.

The dose may be repeated every 4 hours.

No more than four doses should be taken in 24 hours.

Children under 12 years: Not to be given to children under 12 without medical advice.

Elderly: There is no indication that dosage need be modified in the elderly.

4.3 Contraindications

Severe coronary heart disease and cardiovascular disorders. Hypertension. Hyperthyroidism. Contraindicated in patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors. Hypersensitivity to paracetamol, phenylephrine or any other ingredient.

4.4 Special Warnings And Precautions For Use

Use with caution in patients with Raynaud's phenomenon or diabetes mellitus. Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease. Patients should be advised not to take other paracetamol-containing products concurrently.

Label warnings: Do not exceed the stated dose. Keep all medicines out of the reach and sight of children. Contains paracetamol (panel). If symptoms persist consult your doctor. If you are pregnant or are being prescribed medicine by your doctor, seek his advice before taking this product.

Do not take with any other paracetamol-containing products. Immediate medical advice should be sought in the event of an overdose, even if you feel well.

Leaflet: Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Phenylephrine may adversely interact with other sympathomimetics, vasodilators and β-blockers. Drugs which induce hepatic microsomal enzymes, such as alcohol, barbiturates, monoamine oxidase inhibitors and tricyclic antidepressants, may increase the hepatotoxicity of paracetamol, particularly after overdose. Contraindicated in patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors because of the risk of hypertensive crisis.

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

4.6 Pregnancy And Lactation

Due to the vasoconstrictive properties of phenylephrine the product should be used with caution in patients with a history of pre-eclampsia. Phenylephrine may reduce placental perfusion and the product should be used in pregnancy only if the benefits outweigh the risk. There is no information on use in lactation.

Epidemiological studies in human pregnancy have shown no ill-effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol is excreted in breast milk, but not in a clinically significant amount. Available published data do not contraindicate breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Paracetamol: Adverse effects of paracetamol are rare, but hypersensitivity including skin rash may occur. There have been a few reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

Phenylephrine hydrochloride: Rarely, high blood pressure with headache, vomiting and palpitations, which are only likely to occur with overdose. Also rare reports of allergic reactions.

4.9 Overdose

Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. Liver damage is possible in adults who have taken 10g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested) become irreversibly bound to liver tissue.

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any patient who has ingested around 7.5g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N-acetylcysteine, which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

Features of severe overdose of phenylephrine include haemodynamic changes and cardiovascular collapse with respiratory depression. Treatment includes early gastric lavage and symptomatic and supportive measures. Hypertensive effects may be treated with an i.v. α-receptor blocking agent.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol: Paracetamol has both analgesic and antipyretic activity which is believed to be mediated principally through its inhibition of prostaglandin synthesis within the central nervous system.

Phenylephrine: Phenylephrine is a post-synaptic α-receptor agonist with low cardioselective β-receptor affinity and minimal central stimulant activity. It is a recognised decongestant and acts by vasoconstriction to reduce oedema and nasal swelling.

5.2 Pharmacokinetic Properties

Paracetamol: Paracetamol is absorbed rapidly and completely mainly from the small intestine producing peak plasma levels after 15-20 minutes following oral dosing. The systemic availability is subject to first-pass metabolism and varies with dose between 70% and 90%. The drug is rapidly and widely distributed throughout the body and is eliminated from plasma with a T2 of approximately 2 hours. The major metabolites are glucuronide and sulphate conjugates (>80%) which are excreted in urine.

Phenylephrine: Phenylephrine is absorbed from the gastrointestinal tract, but has reduced bioavailability by the oral route due to first-pass metabolism. It retains activity as a nasal decongestant when given orally, the drug distributing through the systemic circulation to the vascular bed of nasal mucosa. When taken by mouth as a nasal decongestant phenylephrine is usually given at intervals of 4-6 hours.

5.3 Preclinical Safety Data

No preclinical findings of relevance have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethyl cellulose

Ascorbic acid

Glyceryl tristearate

Tartaric acid

Sodium carbonate anhydrous

Aspartame

Lemon flavour

Sweet flavour

Xylitol

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C and store in the original package.

6.5 Nature And Contents Of Container

Polyethylene terephthalate/aluminium/polyethylene sachets.

Pack size: 10

6.6 Special Precautions For Disposal And Other Handling

There are no special instructions for handling.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham

NG2 3AA

8. Marketing Authorisation Number(S)

PL00014/0634

9. Date Of First Authorisation/Renewal Of The Authorisation

19 July 2002

10. Date Of Revision Of The Text

August 2006

Midazolam Syrup

Generic Name: midazolam hydrochloride
MIDAZOLAM HYDROCHLORIDE SYRUP CIV

10 mg / 5mL

Rx Only

Midazolam HCl syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. Midazolam HCl syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants (eg, opioids). Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians' and dentists' offices, THAT CAN PROVIDE FOR CONTINUOUS MONITORING OF RESPIRATORY AND CARDIAC FUNCTION. IMMEDIATE AVAILABILITY OF RESUSCITATIVE DRUGS AND AGE- AND SIZE- APPROPRIATE EQUIPMENT FOR VENTILATION AND INTUBATION, AND PERSONNEL TRAINED IN THEIR USE AND SKILLED IN AIRWAY MANAGEMENT SHOULD BE ASSURED (see WARNINGS). For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Midazolam Syrup Description

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration. Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions. Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4] benzodiazepine hydrochloride. Midazolam hydrochloride has the molecular formula C18H13CIFN3•HCl, a calculated molecular weight of 362.25 and the following structural formula:

Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 - 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring. The amount of open-ring form is dependent upon the pH of the solution. At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound. At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions. As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6. Above pH 5, at least 99% of the mixture is present in the closed-ring form.

Midazolam Syrup - Clinical Pharmacology

Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.

Pharmacodynamics

Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepines, include sedative, anxiolytic, amnesic and hypnotic activities. Benzodiazepine pharmacologic effects appear to result from reversible interactions with the γ-amino butyric acid (GABA) benzodiazepine receptor in the CNS, the major inhibitory neurotransmitter in the central nervous system. The action of midazolam is readily reversed by the benzodiazepine receptor antagonist, flumazenil.

Data from published reports of studies in pediatric patients clearly demonstrate that oral midazolam provides safe and effective sedation and anxiolysis prior to surgical procedures that require anesthesia as well as before other procedures that require sedation but may not require anesthesia. The most commonly reported effective doses range from 0.25 to 1 mg/kg in children (6 months to <16 years). The single most commonly reported effective dose is 0.5 mg/kg. Time to onset of effect is most frequently reported as 10 to 20 minutes.

The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

Following premedication with oral midazolam, time to recovery has been assessed in pediatric patients using various measures, such as time to eye opening, time to extubation, time in the recovery room, and time to discharge from the hospital. Most placebo-controlled trials (8 total) have shown little effect of oral midazolam on recovery time from general anesthesia; however, a number of other placebo-controlled studies (5 total) have demonstrated some prolongation in recovery time following premedication with oral midazolam. Prolonged recovery may be related to duration of the surgical procedure and/or use of other medications with central nervous system depressant properties.

Partial or complete impairment of recall following oral midazolam has been demonstrated in several studies. Amnesia for the surgical experience was greater after oral midazolam when used as a premedicant than after placebo and was generally considered a benefit. In one study, 69% of midazolam patients did not remember mask application versus 6% of placebo patients.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been reported in <1% of pediatric patients following premedication (eg, sedation prior to induction of anesthesia) with midazolam HCl syrup; the potential for such adverse events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease (see WARNINGS).

Concomitant use of barbiturates or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation or apnea, and may contribute to profound and/or prolonged drug effect. In one study of pediatric patients undergoing elective repair of congenital cardiac defects, premedication regimens (oral dose of 0.75 mg/kg midazolam or IM morphine plus scopolamine) increased transcutaneous carbon dioxide (PtcCO2), decreased SpO2 (as measured by pulse oximetry), and decreased respiratory rates preferentially in patients with pulmonary hypertension. This suggests that hypercarbia or hypoxia following premedication might pose a risk to children with congenital heart disease and pulmonary hypertension. In a study of an adult population 65 years and older, the preinduction administration of oral midazolam 7.5 mg resulted in a 60% incidence of hypoxemia (paO2<90% for over 30 seconds) at some time during the operative procedure versus 15% for the nonpremedicated group.

Pharmacokinetics

Absorption

Midazolam is rapidly absorbed after oral administration and is subject to substantial intestinal and hepatic first-pass metabolism. The pharmacokinetics of midazolam and its major metabolite, α-hydroxymidazolam, and the absolute bioavailability of midazolam HCl syrup were studied in pediatric patients of different ages (6 months to <16 years old) over a 0.25 to 1 mg/kg dose range. Pharmacokinetic parameters from this study are presented in Table 1. The mean Tmax values across dose groups (0.25, 0.5, and 1 mg/kg) range from 0.17 to 2.65 hours. Midazolam exhibits linear pharmacokinetics between oral doses of 0.25 to 1 mg/kg (up to a maximum dose of 40 mg) across the age groups ranging from 6 months to <16 years. Linearity was also demonstrated across the doses within the age group of 2 years to <12 years having 18 patients at each of the three doses. The absolute bioavailability of the Midazolam Syrup in pediatric patients is about 36%, which is not affected by pediatric age or weight. The AUC0-∞ ratio of α-hydroxymidazolam to midazolam for the oral dose in pediatric patients is higher than for an IV dose (0.38 to 0.75 versus 0.21 to 0.39 across the age group of 6 months to <16 years), and the AUC0-∞ ratio of α-hydroxymidazolam to midazolam for the oral dose is higher in pediatric patients than in adults (0.38 to 0.75 versus 0.40 to 0.56).

Food effect has not been tested using midazolam HCl syrup. When a 15 mg oral tablet of midazolam was administered with food to adults, the absorption and disposition of midazolam was not affected. Feeding is generally contraindicated prior to sedation of pediatric patients for procedures.

Table1. Pharmacokinetics of Midazolam Following Single Dose Administration of Midazolam HCl Syrup

Number of Subjects/age group	Dose (mg/kg)	Tmax (h)	Cmax (ng/mL)	T1/2 (h)	AUC 0-∞ (ng∙h/mL)
6 months to <2 years old
1	0.25	0.17	28.0	5.82	67.6
1	0.50	0.35	66.0	2.22	152
1	1.00	0.17	61.2	2.97	224
2 to <12 years old
18	0.25	0.72 ± 0.44	63.0 ± 30.0	3.16 ± 1.50	138 ± 89.5
18	0.50	0.95 ± 0.53	126 ± 75.8	2.71 ± 1.09	306 ± 196
18	1.00	0.88 ± 0.99	201 ± 101	2.37 ± 0.96	743 ± 642
12 to <16 years old
4	0.25	2.09 ± 1.35	29.1 ± 8.2	6.83 ± 3.84	155 ± 84.6
4	0.50	2.65 ± 1.58	118 ± 81.2	4.35 ± 3.31	821 ± 568
2	1.00	0.55 ± 0.28	191 ± 47.4	2.51 ± 0.18	566 ± 15.7

Distribution

The extent of plasma protein binding of midazolam is moderately high and concentration independent. In adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin. In healthy volunteers, α-hydroxymidazolam is bound to the extent of 89%. In pediatric patients (6 months to <16 years) receiving 0.15 mg/kg IV midazolam, the mean steady-state volume of distribution ranged from 1.24 to 2.02 L/kg.

Metabolism

Midazolam is primarily metabolized in the liver and gut by human cytochrome P450 IIIA4 (CYP3A4) to its pharmacologic active metabolite, α-hydroxymidazolam, followed by glucuronidation of the α–hydroxyl metabolite which is present in unconjugated and conjugated forms in human plasma. The α- hydroxymidazolam glucuronide is then excreted in urine. In a study in which adult volunteers were administered intravenous midazolam (0.1 mg/kg) and α–hydroxymidazolam (0.15 mg/kg), the pharmacodynamic parameter values of the maximum effect (Emax) and concentration eliciting half-maximal effect (EC50) were similar for both compounds. The effects studied were reaction time and errors in tracing tests. The results indicate that α–hydroxymidazolam is equipotent and equally effective as unchanged midazolam on a total plasma concentration basis. After oral or intravenous administration, 63% to 80% of midazolam is recovered in urine as α–hydroxymidazolam glucuronide. No significant amount of parent drug or metabolites is extractable from urine before beta-glucuronidase and sulfatase deconjugation, indicating that the urinary metabolites are excreted mainly as conjugates.

Midazolam is also metabolized to two other minor metabolites: 4-hydroxy metabolite (about 3% of the dose) and 1,4-dihydroxy metabolite (about 1% of the dose) are excreted in small amounts in the urine as conjugates.

Elimination

The mean elimination half-life of midazolam ranged from 2.2 to 6.8 hours following single oral doses of 0.25, 0.5, and 1 mg/kg of midazolam (midazolam HCl syrup). Similar results (ranged from 2.9 to 4.5 hours) for the mean elimination half-life were observed following IV administration of 0.15 mg/kg of midazolam to pediatric patients (6 months to <16 years old). In the same group of patients receiving the 0.15 mg/kg IV dose, the mean total clearance ranged from 9.3 to 11 mL/min/kg.

Pharmacokinetic-Pharmacodynamic Relationships

The relationship between plasma concentration and sedation and anxiolysis scores of oral Midazolam Syrup (single oral doses of 0.25, 0.5, or 1 mg/kg) was investigated in three age groups of pediatric patients (6 months to <2 years, 2 to <12 years, and 12 to <16 years old). In this study, the patient's sedation scores were recorded at baseline and at 10-minute intervals up to 30 minutes after oral dosing until satisfactory sedation ("drowsy" or "asleep but responsive to mild shaking" or "asleep and not responsive to mild shaking") was achieved. Anxiolysis scores were measured at the time when the patient was separated from his/her parents and at mask induction. The results of the analyses showed that the mean midazolam plasma concentration as well as the mean of midazolam plus α–hydroxymidazolam for those patients with a sedation score of 4 (asleep but responsive to mild shaking) is significantly different than the mean concentrations for those patients with a sedation score of 3 (drowsy), which is significantly different than the mean concentrations for patients with a sedation score of 2 (awake/calm). The statistical analysis indicates that the greater the midazolam, or midazolam plus α–hydroxymidazolam concentration, the greater the maximum sedation score for pediatric patients. No such trend was observed between anxiolysis scores and the mean midazolam concentration or mean of midazolam plus α–hydroxymidazolam concentration; however, anxiolysis is a more variable surrogate measurement of clinical response.

Special Populations

Renal Impairment

Although the pharmacokinetics of intravenous midazolam in adult patients with chronic renal failure differed from those of subjects with normal renal function, there were no alterations in the distribution, elimination, or clearance of unbound drug in the renal failure patients. However, the effects of renal impairment on the active metabolite α–hydroxymidazolam are unknown.

Hepatic Dysfunction

Chronic hepatic disease alters the pharmacokinetics of midazolam. Following oral administration of 15 mg of midazolam, Cmax and bioavailability values were 43% and 100% higher, respectively, in adult patients with hepatic cirrhosis than adult subjects with normal liver function. In the same patients with hepatic cirrhosis, following IV administration of 7.5 mg of midazolam, the clearance of midazolam was reduced by about 40% and the elimination half-life was increased by about 90% compared with subjects with normal liver function. Midazolam should be titrated for the desired effect in patients with chronic hepatic disease.

Congestive Heart Failure

Following oral administration of 7.5 mg of midazolam, elimination half-life values were 43% higher in adult patients with congestive heart failure than in control subjects.

Neonates

Midazolam HCl syrup has not been studied in pediatric patients less than 6 months of age.

Drug-Drug Interactions

See PRECAUTIONS: Drug Interactions.

INHIBITORS OF CYP3A4 ISOZYMES

Table 2 summarizes the changes in the Cmax and AUC of midazolam when drugs known to inhibit CYP3A4 were concurrently administered with oral midazolam in adults subjects.

Table 2.

Interacting Drug	Adult Doses Studied	% Increase in Cmax of Oral Midazolam	% Increase in AUC of Oral Midazolam
Cimetidine	800-1200 mg up to qid in divided doses	6-138	10-102
Diltiazem	60 mg tid	105	275
Erythromycin	500 mg tid	170-171	281-341
Fluconazole	200 mg qd	150	250
Grapefruit Juice	200 mL	56	52
Itraconazole	100-200 mg qd	80-240	240-980
Ketoconazole	400 mg qd	309	1490
Ranitidine	150 mg bid or tid;	15-67	9-66
	300 mg qd
Roxithromycin	300 mg qd	37	47
Saquinavir	1200 mg tid	235	514
Verapamil	80 mg tid	97	192

Other drugs known to inhibit the effects of CYP3A4, such as protease inhibitors, would be expected to have similar effects on these midazolam pharmacokinetic parameters.

INDUCERS OF CYP3A4 ISOZYMES

Table 3 summarizes the changes in the Cmax and AUC of midazolam when drugs known to induce CYP3A4 were concurrently administered with oral midazolam in adult subjects. The clinical significance of these changes is unclear.

Table 3.

Interacting Drug	Adult Doses Studied	% Decrease in Cmax of Oral Midazolam	% Decrease in AUC of Oral Midazolam
Carbamazepine	Therapeutic Doses	93	94
Phenytoin	Therapeutic Doses	93	94
Rifampin	600 mg/day	94	96

Although not tested, phenobarbital, rifabutin and other drugs known to induce the effects of CYP3A4 would be expected to have similar effects on these midazolam pharmacokinetic parameters.

Drugs that did not affect midazolam pharmacokinetics are presented in Table 4.

Table 4.

Interacting Drug	Adult Doses Studied
Azithromycin	500 mg/day
Nitrendipine	20 mg
Terbinafine	200 mg/day

Clinical Trials

Dose Ranging, Safety and Efficacy Study With Midazolam HCl Syrup in Pediatric Patients

The effectiveness of midazolam HCl syrup as a premedicant to sedate and calm pediatric patients prior to induction of general anesthesia was compared among three different doses in a randomized, double-blind, parallel-group study. Patients of ASA physical status I, II or III were stratified to 1 of 3 age groups (6 months to <2 years, 2 to <6 years, and 6 to <16 years), and within each age group randomized to 1 of 3 dosing groups (0.25, 0.5, and 1 mg/kg up to a maximum dose of 20 mg). Greater than 90% of treated patients achieved satisfactory sedation and anxiolysis at least one timepoint within 30 minutes posttreatment. Similarly high proportions of patients exhibited satisfactory ease of separation from parent or guardian and were cooperative at the time of mask induction with nitrous oxide and halothane administration. Onset time of satisfactory sedation or anxiolysis occurred within 10 minutes after treatment for >70% of patients who started with an unsatisfactory baseline rating. Whereas pairwise comparisons (0.25 mg/kg versus 0.5 mg/kg groups, and 0.5 mg/kg versus 1 mg/kg groups) on satisfactory sedation did not yield significant p-values (p=0.08 in both cases), comparative analysis of the clinical response between the high and low doses demonstrated that a higher proportion of patients in the 1 mg/kg dose group exhibited satisfactory sedation and anxiolysis as compared to the 0.25 mg/kg group (p<0.05).

Indications and Usage for Midazolam Syrup

Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use (see WARNINGS).

MIDAZOLAM HCl SYRUP MUST BE USED AS SPECIFIED IN THE LABEL.

Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours (see CLINICAL PHARMACOLOGY).

Contraindications

Midazolam HCl syrup is contraindicated in patients with a known hypersensitivity to the drug or allergies to formulation excipients. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction of general anesthesia with injectable midazolam; patients with glaucoma have not been studied.

Warnings

Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam was used in combination with other central nervous system depressants. These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrest (see box WARNING). When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently (see DOSAGE AND ADMINISTRATION).

Prior to the administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age-and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured. Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians' and dentists' offices, that are equipped to provide continuous monitoring of respiratory and cardiac function. Midazolam HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional. If midazolam HCl syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry). Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.

The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because midazolam can depress respiration (see CLINICAL PHARMACOLOGY), especially when used concomitantly with opioid agonists and other sedatives (see DOSAGE AND ADMINISTRATION), it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease.

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. Consideration should be given to the possibility of paradoxical reaction. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Coadministration of oral midazolam in patients who are taking ketoconazole, intraconazole and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to decrease in plasma clearance of midazolam (see PHARMACOKINETICS: Drug-Drug Interactions and PRECAUTIONS). Due to potential for intense and prolonged sedation and respiratory depression, Midazolam Syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.

Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered. Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam. Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Patients with chronic renal failure and patients with congestive heart failure eliminate Midazolam more slowly (see CLINICAL PHARMACOLOGY).

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam HCl syrup (see CLINICAL PHARMACOLOGY) cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. Particular care should be taken to assure safe ambulation.

Usage in Pregnancy

Although midazolam HCl syrup has not been studied in pregnant patients, an increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) have been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.

Usage in Preterm Infants and Neonates

Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Precautions

Use With Other CNS Depressants

The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the CNS. Anticipated effects may range from mild sedation to deep levels of sedation with a potential loss of protective reflexes, particularly when coadministered with anesthetic agents or other CNS depressants. Care must be taken to individualize the dose of midazolam based on the patient's age, underlying medical/surgical conditions, concomitant medications, and to have the personnel, age- and size-appropriate equipment and facilities available for monitoring and intervention. Practitioners administering midazolam must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management.

Use With Inhibitors of CYP3A4 Isozymes

Oral midazolam should be used with caution in patients treated with drugs known to inhibit CYP3A4 because inhibition of metabolism may lead to more intense and prolonged sedation (see PHARMACOKINETICS: Drug-Drug Interactions, and WARNINGS). Patients being treated with medications known to inhibit CYP3A4 isozymes should be treated with lower than recommended doses of midazolam HCl syrup and the clinician should expect a more intense and prolonged effect.

Information for Patients

To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate:

1. Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription. Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.


2. Inform your physician if you are pregnant or are planning to become pregnant.


3. Inform your physician if you are nursing.


4. Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound. The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.


5. Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.


6. For pediatric patients, particular care should be taken to assure safe ambulation.

Drug Interactions

Inhibitors of CYP3A4 Isozymes

Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the Cmax and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when midazolam HCl syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated (see PHARMACOKINETICS: Drug-Drug Interactions).

Inducers of CYP3A4 Isozymes

Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased Cmax and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

CNS Depressants

One case was reported of inadequate sedation with chloral hydrate and later with oral Midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION).

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Drug/Laboratory Test Interactions

Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenesis

Midazolam maleate was administered with diet in mice and rats for 2 years at dosages of 1, 9, and 80 mg/kg/day. In female mice in the highest dose (10 times the highest oral dose of 1 mg/kg for a pediatric patient, on a mg/m2 basis) group there was a marked increase in the incidence of hepatic tumors. In high-dose (19 times the pediatric dose) male rats there was a small but statistically significant increase in benign thyroid follicular cell tumors. Dosages of 9 mg/kg/day of midazolam maleate (1 to 2 times the pediatric dose) did not increase the incidence of tumors in mice or rats. The pathogenesis of induction of these tumors is not known. These tumors were found after chronic administration, whereas human use will ordinarily be single or intermittent doses.

Mutagenesis

Midazolam did not have mutagenic activity in Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79), human lymphocytes or in the micronucleus test in mice.

Impairment of Fertility

A reproduction study in male and female rats did not show any impairment of fertility at dosages up to 16 mg/kg/day PO (3 times the human dose of 1 mg/kg, on a mg/m2 basis).

Pregnancy

Teratogenic Effects

Pregnancy Category D

(see WARNINGS).

Embryo-fetal development studies, performed with midazolam maleate in mice (at up to 120 mg/kg/day PO, 10 times the human dose of 1 mg/kg on a mg/m2 basis), rats (at up to 4 mg/kg/day IV, 8 times the human IV dose of 5 mg) and rabbits (at up to 100 mg/kg/day PO, 32 times the human oral dose of 1 mg/kg on a mg/m2 basis), did not show evidence of teratogenicity.

Nonteratogenic Effects

Studies in rats showed no adverse effects on reproductive parameters during gestation and lactation. Dosages tested (4 mg/kg IV and 50 mg/kg PO) were approximately 8 times each of the human doses on a mg/m2 basis.

Labor and Delivery

In humans, measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum and amniotic fluid, indicating placental transfer of the drug.

The use of midazolam HCl syrup in obstetrics has not been evaluated in clinical studies. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression, Midazolam Syrup is not recommended for obstetrical use.

Nursing Mothers

Midazolam is excreted in human milk. Caution should be exercised when Midazolam Syrup is administered to a nursing woman.

Geriatric Use

The safety and efficacy of this product have not been fully studied in geriatric patients. Therefore, there are no available data on a safe dosing regimen. One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO2<90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group. Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease

Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects. One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crises that had been triggered by premedication. In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects. Both premedication regimens increased PtcCO2 and decreased SpO2 and respiratory rates preferentially in patients with pulmonary hypertension.

Adverse Reactions

The distribution of adverse events occurring in patients evaluated in a randomized, double-blind, parallel-group trial are presented in Tables 5 and 6 by body system in order of decreasing frequency: for the premedication period (eg, sedation period prior to induction of anesthesia) alone, see Table 5; for over the entire monitoring period including premedication, anesthesia and recovery, see Table 6.

The distribution of adverse events occurring during the premedication period, before induction of anesthesia, is presented in Table 5. Emesis which occurred in 31/397 (8%) patients over the entire monitoring period, occurred in 3/397 (0.8%) of patients during the premedication period (from midazolam administration to mask induction). Nausea, which occurred in 14/397 (4%) patients over the entire monitoring period (premedication, anesthesia and recovery), occurred in 2/397 (0.5%) patients during the premedication period.

This distribution of all adverse events occurring in ≥1% of patients over the entire monitoring period are presented in Table 6. For the entire monitoring period (premedication, anesthesia and recovery), adverse events were reported by 82/397 (21%) patients who received midazolam overall. The most frequently reported adverse events were emesis occurring in 31/397 (8%) patients and nausea occurring in 14/397 (4%) patients. Most of these gastrointestinal events occurred after the administration of other anesthetic agents.

For the respiratory system overall, adverse events (hypoxia, laryngospasm, rhonchi, coughing, respiratory depression, airway obstruction, upper-airway congestion, shallow respirations), occurred during the entire monitoring period in 31/397 (8%) patients and increased in frequency as dosage was increased: 7/132 (5%) patients in the 0.25 mg/kg dose group, 9/132 (7%) patients in the 0.5 mg/kg dose group, and 15/133 (11%) patients in the 1 mg/kg dose group.

Most of the respiratory adverse events occurred during induction, general anesthesia or recovery. One patient (0.25%) experienced a respiratory system adverse event (laryngospasm) during the premedication period. This adverse event occurred precisely at the time of induction. Although many of the respiratory complications occurred in settings of mupper airway procedures or concurrently administered opioids, a number of these events occurred outside of these settings as well. In this study, administration of midazolam HCl syrup was generally accompanied by a slight decrease in both systolic and diastolic blood pressures, as well as a slight increase in heart rate.

Table 5. Adverse Events Occurring During the Premedication Period Before Mask Induction in the Randomized, Double-Blind, Parallel-Group Trial

Body System	Treatment Regimen			Overall
No. Patients with Adverse Events	0.25 mg/kg (n=132) No. (%)	0.5 mg/kg (n=132) No. (%)	1 mg/kg (n=133) No. (%)	(n=397)   No. (%)
* This adverse event occurred precisely at the time of induction.
Gastrointestinal System Disorders
Emesis	1 (0.76%)	1 (0.76%)	1 (0.75%)	3 (0.76%)
Nausea			2 (1.5%)	2 (0.50%)
Respiratory System Disorders