Epivir-HBV

Pronunciation: la-MIH-vyoo-deen
Generic Name: Lamivudine
Brand Name: Epivir-HBV

High levels of lactic acid in the blood and severe, life-threatening liver problems have been reported with the use of Epivir-HBV alone or with other medicines. HIV counseling and testing should be offered to all patients before treatment for hepatitis B virus is started with Epivir-HBV and periodically during treatment. Epivir-HBV has a lower dose of the same active ingredient (lamivudine) than in Epivir, a medicine used to treat HIV infection. These formulations are not interchangeable. If Epivir-HBV is prescribed for a patient with hepatitis B virus and undiagnosed or untreated HIV infection, the HIV infection will be less treatable with Epivir-HBV and other medicines. Worsening of hepatitis B virus infection has been reported in patients who stop taking Epivir-HBV. Patients should have their liver function monitored closely for at least several months after stopping use of Epivir-HBV.

Epivir-HBV is used for:

Treating certain types of chronic hepatitis B virus infection.

Epivir-HBV is a nucleoside analogue. It works by reducing the amount of hepatitis B virus in the body by blocking the ability of the virus to multiply and infect new liver cells.

Do NOT use Epivir-HBV if:

• you are allergic to any ingredient in Epivir-HBV


• you have HIV infection, abnormal liver function tests, severe liver problems, or lactic acidosis


• you are taking zalcitabine or another medicine containing lamivudine

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

Before using Epivir-HBV:

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

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


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


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


• if you have muscle problems, swelling of the pancreas, abnormal blood counts, liver or kidney problems, diabetes, or a nerve disorder

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

• Trimethoprim/sulfamethoxazole because it may increase the risk of Epivir-HBV's side effects


• Zalcitabine because it may decrease Epivir-HBV's effectiveness

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

How to use Epivir-HBV:

Use Epivir-HBV as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Epivir-HBV. Talk to your pharmacist if you have questions about this information.


• Take Epivir-HBV by mouth with or without food.


• Continue to take Epivir-HBV even if you feel well. Do not miss any doses.


• It is important not to miss any doses of Epivir-HBV. Taking Epivir-HBV at the same time each day will help you remember to take it.


• If you miss a dose of Epivir-HBV, take it as soon as possible. If it is within 2 hours of your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Epivir-HBV.

Important safety information:

• Epivir-HBV may cause drowsiness or dizziness. These effects may be worse if you take it with alcohol or certain medicines. Use Epivir-HBV with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Your doctor will offer you counseling and testing for HIV infection (the virus that causes AIDS) before treatment with Epivir-HBV and periodically during treatment. You should not take Epivir-HBV if you have HIV infection. If you have both hepatitis B virus and HIV, make sure that your doctor knows you have both infections. If you are prescribed lamivudine, you should only use the medicine that is for HIV treatment ( Epivir). The lower dose of lamivudine in Epivir-HBV could make the HIV infection harder to treat.


• Epivir-HBV is not a cure for hepatitis B virus infection. It is unknown if Epivir-HBV reduces the risk of liver cancer or cirrhosis that may be caused by hepatitis B virus. Some patients developed hepatitis B virus that is resistant to Epivir-HBV. These patients had less benefit from Epivir-HBV and some experienced worsening of hepatitis after the resistant virus appeared.


• Your doctor will perform lab tests for several months after you stop taking Epivir-HBV. Some patients have had worsening hepatitis B virus after stopping use of Epivir-HBV. Tell your doctor about any new or unusual symptoms that you notice after stopping treatment.


• Epivir-HBV has not been shown to reduce the risk of passing hepatitis B to other people through sexual contact or blood contamination. Use barrier forms of contraception (eg, condoms) if you are infected with hepatitis B virus.


• Diabetes patients - Epivir-HBV contains sucrose and may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Lab tests, including liver and kidney function tests, may be performed while you use Epivir-HBV. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Caution is advised when using Epivir-HBV in CHILDREN with a history of swelling of the pancreas. Epivir-HBV should not be used in CHILDREN younger than 2 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Epivir-HBV while you are pregnant. Epivir-HBV is found in breast milk. Do not breast-feed while taking Epivir-HBV.

Possible side effects of Epivir-HBV:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Changes in body fat; chills; coughing; decreased appetite; diarrhea; difficulty sleeping; dizziness; ear, nose, and throat infection; general body discomfort; headache; indigestion; joint pain; muscle pain; nausea; sinus drainage; sore throat; stomach discomfort; tiredness.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); dark urine; depression (mental or mood changes); enlarged stomach; increased heart rate; numbness or tingling in the arms or legs; persistent sore throat, chills, or fever; severe muscle or joint pain; stomach tenderness or pain; unusual bleeding or bruising; unusual weakness or exhaustion; vomiting; yellowing of the skin or eyes.

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

See also: Epivir-HBV side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Epivir-HBV:

Store Epivir-HBV at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Epivir-HBV out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Epivir-HBV resources

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

Compare Epivir-HBV with other medications

• Hepatitis B
• HIV Infection
• Nonoccupational Exposure
• Occupational Exposure

Avandaryl

rosiglitazone maleate and glimepiride

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

WARNING: CONGESTIVE HEART FAILURE AND MYOCARDIAL INFARCTION

• Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.2)]. After initiation of Avandaryl, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of Avandaryl must be considered.


• Avandaryl is not recommended in patients with symptomatic heart failure. Initiation of Avandaryl in patients with established NYHA Class III or IV heart failure is contraindicated. [See Contraindications (4) and Warnings and Precautions (5.2).]


• A meta-analysis of 52 clinical trials (mean duration 6 months; 16,995 total patients), most of which compared rosiglitazone to placebo, showed rosiglitazone to be associated with an increased risk of myocardial infarction. Three other trials (mean duration 46 months; 14,067 total patients), comparing rosiglitazone to some other approved oral antidiabetic agents or placebo, showed a statistically non-significant increased risk of myocardial infarction, and a statistically non-significant decreased risk of death. There have been no clinical trials directly comparing cardiovascular risk of rosiglitazone and ACTOS® (pioglitazone, another thiazolidinedione), but in a separate trial, pioglitazone (when compared to placebo) did not show an increased risk of myocardial infarction or death. [See Warnings and Precautions (5.3).]

Indications and Usage for Avandaryl

After consultation with a healthcare professional who has considered and advised the patient of the risks and benefits of rosiglitazone, Avandaryl® is indicated as an adjunct to diet and exercise to improve glycemic control when treatment with both rosiglitazone and glimepiride is appropriate in adults with type 2 diabetes mellitus who either are:

•  already taking rosiglitazone, or


•  not already taking rosiglitazone and unable to achieve glycemic control on other diabetes medications and, in consultation with their healthcare provider, have decided not to take pioglitazone (ACTOS®) or pioglitazone-containing products (ACTOSPLUS MET®, ACTOPLUS MET XR®, DUETACT®) for medical reasons.

Other Important Limitations of Use:

• Due to its mechanism of action, rosiglitazone is active only in the presence of endogenous insulin. Therefore, Avandaryl should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.


• Coadministration of Avandaryl with insulin is not recommended [see Warnings and Precautions (5.2, 5.3)].

Avandaryl Dosage and Administration

 Prior to prescribing Avandaryl, refer to Indications and Usage (1) for appropriate patient selection.

Starting Dose

The recommended starting dose is 4 mg/1 mg administered once daily with the first meal of the day. For adults already treated with a sulfonylurea or rosiglitazone, a starting dose of 4 mg/2 mg may be considered.

All patients should start the rosiglitazone component of Avandaryl at the lowest recommended dose. Further increases in the dose of rosiglitazone should be accompanied by careful monitoring for adverse events related to fluid retention [see Boxed Warning and Warnings and Precautions (5.5)].

When switching from combination therapy of rosiglitazone plus glimepiride as separate tablets, the usual starting dose of Avandaryl is the dose of rosiglitazone and glimepiride already being taken.

Dose Titration

Dose increases should be individualized according to the glycemic response of the patient. Patients who may be more sensitive to glimepiride [see Warnings and Precautions (5.4)], including the elderly, debilitated, or malnourished, and those with renal, hepatic, or adrenal insufficiency, should be carefully titrated to avoid hypoglycemia. If hypoglycemia occurs during up-titration of the dose or while maintained on therapy, a dosage reduction of the glimepiride component of Avandaryl may be considered. Increases in the dose of rosiglitazone should be accompanied by careful monitoring for adverse events related to fluid retention [see Boxed Warning and Warnings and Precautions (5.5)].

To switch to Avandaryl for adults currently treated with rosiglitazone, dose titration of the glimepiride component of Avandaryl is recommended if patients are not adequately controlled after 1 to 2 weeks. The glimepiride component may be increased in no more than 2 mg increments. After an increase in the dosage of the glimepiride component, dose titration of Avandaryl is recommended if patients are not adequately controlled after 1 to 2 weeks.

To switch to Avandaryl for adults currently treated with sulfonylurea, it may take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see the full effect of the rosiglitazone component. Therefore, dose titration of the rosiglitazone component of Avandaryl is recommended if patients are not adequately controlled after 8 to 12 weeks. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to Avandaryl due to potential overlapping of drug effect. After an increase in the dosage of the rosiglitazone component, dose titration of Avandaryl is recommended if patients are not adequately controlled after 2 to 3 months.

Maximum Dose

The maximum recommended daily dose is 8 mg rosiglitazone and 4 mg glimepiride.

Specific Patient Populations

Elderly and Malnourished Patients and Those With Renal, Hepatic, or Adrenal Insufficiency: In elderly, debilitated, or malnourished patients, or in patients with renal, hepatic, or adrenal insufficiency, the starting dose, dose increments, and maintenance dosage of Avandaryl should be conservative to avoid hypoglycemic reactions. [See Warnings and Precautions (5.4) and Clinical Pharmacology (12.3).]

Hepatic Impairment: Liver enzymes should be measured prior to initiating treatment with Avandaryl. Therapy with Avandaryl should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X upper limit of normal at start of therapy). After initiation of Avandaryl, liver enzymes should be monitored periodically per the clinical judgment of the healthcare professional. [See Warnings and Precautions (5.7) and Clinical Pharmacology (12.3).]

Pregnancy and Lactation: Avandaryl should not be used during pregnancy or in nursing mothers.

Pediatric Use: Safety and effectiveness of Avandaryl in pediatric patients have not been established. Avandaryl and its components, rosiglitazone and glimepiride, are not recommended for use in pediatric patients.

Dosage Forms and Strengths

Each rounded triangular tablet contains rosiglitazone maleate and glimepiride as follows:

• 4 mg/1 mg – yellow, gsk debossed on one side and 4/1 on the other.


• 4 mg/2 mg – orange, gsk debossed on one side and 4/2 on the other.


• 4 mg/4 mg – pink, gsk debossed on one side and 4/4 on the other.


• 8 mg/2 mg – pale pink, gsk debossed on one side and 8/2 on the other.


• 8 mg/4 mg – red, gsk debossed on one side and 8/4 on the other.

Contraindications

Initiation of Avandaryl in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Boxed Warning].

Warnings and Precautions

Increased Risk of Cardiovascular Mortality for Sulfonylurea Drugs

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the trial conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The trial involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 1970;19[Suppl. 2]:747-830). UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the trial to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP trial provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride-containing tablets and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this trial, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

Cardiac Failure With Rosiglitazone

Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered [see Boxed Warning].

Patients with congestive heart failure (CHF) NYHA Class I and II treated with rosiglitazone have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled echocardiographic trial was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed with rosiglitazone treatment compared to placebo during the 52-week trial. (See Table 1.)

Table 1. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With Rosiglitazone or Placebo (in Addition to Background Antidiabetic and CHF Therapy)

Events	Rosiglitazone	Placebo
	N = 110 n (%)	N = 114 n (%)
Adjudicated
Cardiovascular deaths	5 (5%)	4 (4%)
CHF worsening	7 (6%)	4 (4%)
– with overnight hospitalization	5 (5%)	4 (4%)
– without overnight hospitalization	2 (2%)	0 (0%)
New or worsening edema	28 (25%)	10 (9%)
New or worsening dyspnea	29 (26%)	19 (17%)
Increases in CHF medication	36 (33%)	20 (18%)
Cardiovascular hospitalizationa	21 (19%)	15 (13%)
Investigator-reported, non-adjudicated
Ischemic adverse events	10 (9%)	5 (4%)
– Myocardial infarction	5 (5%)	2 (2%)
– Angina	6 (5%)	3 (3%)

aIncludes hospitalization for any cardiovascular reason.

Initiation of Avandaryl in patients with established NYHA Class III or IV heart failure is contraindicated. Avandaryl is not recommended in patients with symptomatic heart failure. [See Boxed Warning.]

Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of Avandaryl is not recommended for patients experiencing an acute coronary event, and discontinuation of Avandaryl during this acute phase should be considered.

Patients with NYHA Class III and IV cardiac status (with or without CHF) have not been studied in controlled clinical trials. Avandaryl is not recommended in patients with NYHA Class III and IV cardiac status.

 Congestive Heart Failure During Coadministration of Rosiglitazone With Insulin: In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure. Coadministration of rosiglitazone and insulin is not recommended. [See Indications and Usage (1) and Warnings and Precautions (5.3).]

 In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis1 [see Warnings and Precautions (5.3)], patients with type 2 diabetes mellitus were randomized to coadministration of rosiglitazone and insulin (N = 1,018) or insulin (N = 815). In these 7 trials, rosiglitazone was added to insulin. These trials included patients with long-standing diabetes (median duration of 12 years) and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. The total number of patients with emergent congestive heart failure was 23 (2.3%) and 8 (1.0%) in the rosiglitazone plus insulin and insulin groups, respectively.

 Heart Failure in Observational Studies of Elderly Diabetic Patients Comparing Rosiglitazone to Pioglitazone: Three observational studies2-4 in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of hospitalized heart failure compared to use of pioglitazone. One other observational study5 in patients with a mean age of 54 years, which also included an analysis in a subpopulation of patients >65 years of age, found no statistically significant increase in emergency department visits or hospitalization for heart failure in patients treated with rosiglitazone compared to pioglitazone in the older subgroup.

Major Adverse Cardiovascular Events

 Cardiovascular adverse events have been evaluated in a meta-analysis of 52 clinical trials, in long-term, prospective, randomized, controlled trials, and in observational studies.

 Meta-Analysis of Major Adverse Cardiovascular Events in a Group of 52 Clinical Trials: A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 52 double-blind, randomized, controlled clinical trials (mean duration 6 months).1 These trials had been conducted to assess glucose-lowering efficacy in type 2 diabetes. Prospectively planned adjudication of cardiovascular events did not occur in most of the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled trials included monotherapy trials (monotherapy with rosiglitazone versus placebo monotherapy) and add-on trials (rosiglitazone or placebo, added to sulfonylurea, metformin, or insulin). Active control trials included monotherapy trials (monotherapy with rosiglitazone versus sulfonylurea or metformin monotherapy) and add-on trials (rosiglitazone plus sulfonylurea or rosiglitazone plus metformin, versus sulfonylurea plus metformin). A total of 16,995 patients were included (10,039 in treatment groups containing rosiglitazone, 6,956 in comparator groups), with 5,167 patient-years of exposure to rosiglitazone and 3,637 patient-years of exposure to comparator. Cardiovascular events occurred more frequently for patients who received rosiglitazone than for patients who received comparators (see Table 2).

Table 2. Occurrence of Cardiovascular Events in a Meta-Analysis of 52 Clinical Trials

Eventa	Rosiglitazone  (N=10,039)  n (%)	Comparator  (N=6,956)  n (%)
MACE (a composite of myocardial infarction, cardiovascular death, or stroke)	70 (0.7)	39 (0.6)
Myocardial Infarction	45 (0.4)	20 (0.3)
Cardiovascular Death	17 (0.2)	9 (0.1)
Stroke	18 (0.2)	16 (0.2)
All-cause Death	29 (0.3)	17 (0.2)

 a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).

  In this analysis, a statistically significant increased risk of myocardial infarction with rosiglitazone versus pooled comparators was observed. Analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death), referred to hereafter as MACE. Rosiglitazone had a statistically non-significant increased risk of MACE compared to the pooled comparators. A statistically significant increased risk of myocardial infarction and statistically non-significant increased risk of MACE with rosiglitazone was observed in the placebo-controlled trials. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. (See Figure 1 and Table 3.)

Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for MACE and Myocardial Infarction in the Meta-Analysis of 52 Clinical Trials

Table 3. Occurrence of MACE and Myocardial Infarction in a Meta-Analysis of 52 Clinical Trials by Trial Type

			MACE		Myocardial Infarction
		N	n (%)	OR  (95%CI)	n (%)	OR  (95%CI)
Active-  Controlled Trials	RSG	2,119	16 (0.8%)	1.05	10 (0.5%)	1.00
	Control	1,918	14 (0.7%)	(0.48, 2.34)	9 (0.5%)	(0.36, 2.82)
Placebo-  Controlled Trials	RSG	8,124	54 (0.7%)	1.53	35 (0.4%)	2.23
	Placebo	5,636	28 (0.5%)	(0.94, 2.54)	13 (0.2%)	(1.14, 4.64)
Overall	RSG	10,039	70 (0.7%)	1.44	45 (0.4%)	1.8
	Control	6,956	39 (0.6%)	(0.95, 2.20)	20 (0.3%)	(1.03, 3.25)

 RSG = rosiglitazone

 Of the placebo-controlled trials in the meta-analysis, 7 trials had patients randomized to rosiglitazone plus insulin or insulin. There were more patients in the rosiglitazone plus insulin group compared to the insulin group with myocardial infarctions, MACE, cardiovascular deaths, and all-cause deaths (see Table 4). The total number of patients with stroke was 5 (0.5%) and 4 (0.5%) in the rosiglitazone plus insulin and insulin groups, respectively. The use of rosiglitazone in combination with insulin may increase the risk of myocardial infarction [See Warnings and Precautions (5.1).]

Table 4. Occurrence of Cardiovascular Events for Rosiglitazone in Combination With Insulin in a Meta-Analysis of 52 Clinical Trials

Eventa	Rosiglitazone  (N=1,018)  (%)	Insulin  (N = 815)  (%)	OR (95% CI)
MACE (a composite of myocardial infarction, cardiovascular death, or stroke)	1.3	0.6	2.14 (0.70, 7.83)
Myocardial infarction	0.6	0.1	5.6 (0.67, 262.7)
Cardiovascular death	0.4	0.0	ND, (0.47, ∞)
All cause death	0.6	0.2	2.19 (0.38, 22.61)

 ND = not defined

 a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).

 Myocardial Infarction Events in Large, Long-Term, Prospective, Randomized, Controlled Trials of Rosiglitazone: Data from 3 large, long-term, prospective, randomized, controlled clinical trials of rosiglitazone were assessed separately from the meta-analysis.6-8 These 3 trials included a total of 14,067 patients (treatment groups containing rosiglitazone N = 6,311; comparator groups N = 7,756), with patient-year exposure of 24,534 patient-years for rosiglitazone and 28,882 patient-years for comparator. Patient populations in the trials included patients with impaired glucose tolerance, patients with type 2 diabetes who were initiating oral agent monotherapy, and patients with type 2 diabetes who had failed monotherapy and were initiating dual oral agent therapy. Duration of follow-up exceeded 3 years in each trial.

 In each of these trials, there was a statistically non-significant increase in the risk of myocardial infarction for rosiglitazone versus comparator medications.

 In a long-term, randomized, placebo-controlled, 2x2 factorial trial intended to evaluate rosiglitazone, and separately ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes in 5,269 subjects with glucose intolerance, the incidence of myocardial infarction was higher in the subset of subjects who received rosiglitazone in combination with ramipril than among subjects who received ramipril alone but not in the subset of subjects who received rosiglitazone alone compared to placebo.6 The higher incidence of myocardial infarction among subjects who received rosiglitazone in combination with ramipril was not confirmed in the two other large (total N = 8,798) long-term, randomized, active-controlled clinical trials conducted in patients with type 2 diabetes, in which 30% and 40% of patients in the two trials reported angiotensin-converting enzyme inhibitor use at baseline.7,8

 There have been no adequately designed clinical trials directly comparing rosiglitazone to pioglitazone on cardiovascular risks. However, in a long-term, randomized, placebo-controlled cardiovascular outcomes trial comparing pioglitazone to placebo in patients with type 2 diabetes mellitus and prior macrovascular disease, pioglitazone was not associated with an increased risk of myocardial infarction or total mortality.9

 The increased risk of myocardial infarction observed in the meta-analysis and large, long-term controlled clinical trials, and the increased risk of MACE observed in the meta-analysis described above, have not translated into a consistent finding of excess mortality from controlled clinical trials or observational studies. Clinical trials have not shown any difference between rosiglitazone and comparator medications in overall mortality or CV-related mortality.

 Mortality in Observational Studies of Rosiglitazone Compared to Pioglitazone: Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of all-cause mortality compared to use of ACTOS (pioglitazone).2-4 One observational study5 in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with rosiglitazone compared to ACTOS (pioglitazone) and reported similar results in the subpopulation of patients >65 years of age. One additional small, prospective, observational study10 found no statistically significant differences for CV mortality and all-cause mortality in patients treated with rosiglitazone compared to ACTOS (pioglitazone).

Hypoglycemia

Avandaryl is a combination tablet containing rosiglitazone and glimepiride, a sulfonylurea. All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. Debilitated or malnourished patients, and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. A starting dose of 1 mg glimepiride, as contained in Avandaryl 4 mg/1 mg, followed by appropriate dose titration is recommended in these patients. [See Clinical Pharmacology (12.3).] Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.

Patients receiving rosiglitazone in combination with a sulfonylurea may be at risk for hypoglycemia, and a reduction in the dose of the sulfonylurea may be necessary [see Dosage and Administration (2.2)].

Edema

Avandaryl should be used with caution in patients with edema. In a clinical trial in healthy volunteers who received 8 mg of rosiglitazone once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo.

Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Avandaryl should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure [see Boxed Warning, Warnings and Precautions (5.2), and Patient Counseling Information (17.1)].

In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with rosiglitazone, and may be dose-related. Patients with ongoing edema were more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone [see Adverse Reactions (6.1)]. The use of Avandaryl in combination with insulin is not recommended[see Warnings and Precautions (5.2, 5.3)].

Weight Gain

Dose-related weight gain was seen with Avandaryl, rosiglitazone alone, and rosiglitazone together with other hypoglycemic agents (see Table 5). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Table 5. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials [Median (25th, 75th, Percentile)]

Monotherapy
Duration	Control Group		Rosiglitazone 4 mg	Rosiglitazone 8 mg
26 weeks	Placebo	-0.9 (-2.8, 0.9) N = 210	1.0 (-0.9, 3.6) N = 436	3.1 (1.1, 5.8) N = 439
52 weeks	Sulfonylurea	2.0 (0, 4.0) N = 173	2.0 (-0.6, 4.0) N = 150	2.6 (0, 5.3) N = 157
Combination Therapy
			Rosiglitazone + Control Therapy
Duration	Control Group		Rosiglitazone 4 mg	Rosiglitazone 8 mg
24-26 weeks	Sulfonylurea	0 (-1.0, 1.3) N = 1,155	2.2 (0.5, 4.0) N = 613	3.5 (1.4, 5.9) N = 841
26 weeks	Metformin	-1.4 (-3.2, 0.2) N = 175	0.8 (-1.0, 2.6) N = 100	2.1 (0, 4.3) N = 184
26 weeks	Insulin	0.9 (-0.5, 2.7) N = 162	4.1 (1.4, 6.3) N = 164	5.4 (3.4, 7.3) N = 150

In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication, the median weight change (25th, 75th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for rosiglitazone, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.

In postmarketing experience with rosiglitazone alone or in combination with other hypoglycemic agents, there have been rare reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning].

Hepatic Effects

With sulfonylureas, including glimepiride, there may be an elevation of liver enzyme levels in rare cases. In isolated instances, impairment of liver function (e.g., with cholestasis and jaundice), as well as hepatitis (which may also lead to liver failure) have been reported.

Liver enzymes should be measured prior to the initiation of therapy with Avandaryl in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with Avandaryl should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤2.5X upper limit of normal) at baseline or during therapy with Avandaryl should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with Avandaryl in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with Avandaryl, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with Avandaryl should be discontinued.

If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with Avandaryl should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

Macular Edema

Macular edema has been reported in postmarketing experience in some diabetic patients who were taking rosiglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient’s underlying medications or other physical findings. [See Adverse Reactions (6.3).]

Fractures

In a 4- to 6-year comparative trial (ADOPT) of glycemic control with monotherapy in drug-naïve patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking rosiglitazone. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for rosiglitazone versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the trial. The majority of the fractures in the women who received rosiglitazone occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). Other trials suggest that this risk may also apply to men, although the risk of fracture among women appears higher than that among men. The risk of fracture should be considered in the care of patients treated with rosiglitazone, and attention given to assessing and maintaining bone health according to current standards of care.

Hematologic Effects

Decreases in hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone [see Adverse Reactions (6.2)]. The observed changes may be related to the increased plasma volume observed with treatment with rosiglitazone.

Hemolytic Anemia

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glimepiride, a component of Avandaryl, belongs to the class of sulfonylurea agents, caution

Papaverine Hydrochloride

Class: Vasodilating Agents, Miscellaneous
VA Class: CV900
CAS Number: 61-25-6
Brands: Para-Time SR

Introduction

Vasodilating agent;^{180 181 a} benzylisoquinoline alkaloid^{180 181 a} prepared synthetically or obtained from opium.^a

Uses for Papaverine Hydrochloride

Cardiac and Vascular Uses

Relief of cerebral and peripheral ischemia associated with arterial spasm and myocardial ischemia complicated by arrhythmias.^{180 181 a}

Has been used IV and intra-arterially in treatment of acute vascular occlusion in conjunction with anticoagulants.^a

Treatment of angina pectoris;¹⁸¹ results not impressive at usual dosages.^a Not recommended as a substitute for nitroglycerin in anginal attacks.^a

Has been used in the treatment of other cardiovascular or vascular conditions including vascular encephalopathy associated with hypertensive disease, certain cerebral angiospastic states, and chronic peripheral vascular diseases (i.e., Raynaud’s syndrome, Buerger’s disease); however, use in these conditions has been superseded by more effective agents.^a

Erectile Dysfunction

Self-treatment of erectile dysfunction† (ED, impotence).¹⁷⁸

Has been used alone or in combination with phentolamine and/or alprostadil in patients with neurogenic^{103 105 106 108 110 112 113 115 116 118 119 120 128 129 132} and/or limited vasculogenic impotence ^{103 105 106 108 110 112 113 115 116 120 121 128 129 132} or those with psychogenic impotence,^{105 106 108 120 128 129 132} but efficacy in patients with a vasculogenic component of their impotence may be variable depending on the extent and type of vascular dysfunction.^{103 108 110 115 120 128 129}

The goal of therapy is to provide an erection of adequate rigidity and duration to be sexually functional while avoiding prolonged erection or priapism.^{142 143 144 145 146 147}

Some experts (American Urological Association [AUA]) recommend that selective phosphodiesterase (PDE) type 5 inhibitor therapy (sildenafil, tadalafil, vardenafil) be offered as first-line erectile dysfunction treatment unless contraindicated.¹⁷⁸

Intracavernosal therapy with papaverine and/or other drugs generally reserved for patients who do not respond to psychotherapy/behavioral therapy, vacuum constriction devices, and/or selective PDE type 5 inhibitors and in whom attempts at identifying and modifying any drug-related (e.g., certain antihypertensive agents) or other potential reversible medical cause of erectile dysfunction have proved inadequate.^{110 130}

Some clinicians currently prefer alprostadil, alone or combined with other agents, when intracavernosal treatment of impotence is indicated because of possible improved efficacy and decreased adverse effects (e.g., priapism, fibrotic changes) compared with papaverine therapy.^{130 149 150 151 152 153 154}

Choice of therapy for erectile dysfunction should be individualized taking into account differences in response, tolerability and safety, administration considerations, cost and patient reimbursement factors, experience and judgment of the clinician, and individual patient and partner preference, expectations, and satisfaction.^{170 171 172 173 174 175 176 177 178}

Do not use for enhancing erections in men who are not impotent.¹⁵⁴

Other Uses

Has been used in the treatment of GI spasms, dysmenorrhea, biliary or ureteral colic, bronchial asthma, cardiac arrhythmias, and other pathologic conditions†;^{181 a} however, insufficient evidence to establish therapeutic value.^a

Papaverine Hydrochloride Dosage and Administration

Administration

Administer orally, or by IM or slow IV injection.^{180 181 a}

Has been used intra-arterially in treatment of acute vascular occlusion in conjunction with anticoagulants.^a

Has been administered by intracavernous† injection for the treatment of erectile dysfunction.^{103 105 106 107 108 110 112 113 114 115 116 118 119 120 121 122 123 124 125 126 127}

IV Administration

Slow IV injection preferred when an immediate effect is desired.^{181 a}

Rate of Administration

Inject slowly over a 1- to 2-minute period to minimize serious adverse effects (e.g., arrhythmias, fatal apnea).^{181 a} (See Cardiovascular and Respiratory Effects under Cautions.)

Dosage

Available as papaverine hydrochloride; dosage expressed in terms of salt.^{180 181}

Pediatric Patients

Cardiac and Vascular Use†

IV or IM

6 mg/kg daily (as 4 divided doses).^a

Adults

Cardiac and Vascular Use

Oral

Usually, 150 mg (extended-release capsules) every 8–12 hours.^{180 a}

Alternatively, 300 mg (extended-release capsules) every 12 hours.^a

75–300 mg (conventional tablets [no longer commercially available in US] 3–5 times daily, also has been used.^a

IV or IM

Usually, 30 mg; may repeat 30–120 mg every 3 hours as necessary.^{181 a}

Cardiac extrasystoles: May administer 2 doses 10 minutes apart.^{181 a}

Erectile Dysfunction†

Intracavernosal Self-injection†

2.5–37.5 mg.¹⁷⁸ Usually, titrated up to 30 mg in combination with phentolamine mesylate 0.5–1 mg (range: 0.08–1.25 mg).¹⁷⁸

Tolerance with long-term use may require dosage increase.^{105 114 129}

Prescribing Limits

Adults

Cardiovascular Use

IV

960 mg daily.

Special Populations

No special population dosage recommendations at this time.^{180 181}

Cautions for Papaverine Hydrochloride

Contraindications

• 
  

  Complete atrioventricular heart block.^{181 a}

  
  


• 
  

  Administer with extreme caution when cardiac conduction is depressed, because of increased risk of transient ectopic rhythms of ventricular origin (premature beats or paroxysmal tachycardia).^{181 a}

  
  

Warnings/Precautions

Warnings

Cardiovascular and Respiratory Effects

Administer IV slowly with caution; rapid injection may result in arrhythmias and fatal apnea.^a

Large parenteral doses can depress atrioventricular and intraventricular conduction; may result in serious arrhythmias.¹⁸⁰

Vasoactive Therapy

While some manufacturers have stated that papaverine hydrochloride injection is not indicated for the treatment of impotence via intracorporeal injection,^{133 134 135 181} the drug has been employed effectively via intracavernosal injection.^{103 105 106 107 108 110 112 113 114 115 116 118 119 120 121 126 128 130 132 137 142}

Do not use vasoactive therapy for impotence in patients who might have conditions predisposing to priapism (e.g., sickle cell anemia or trait, multiple myeloma, leukemia), in those with anatomic deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie’s disease), or in men in whom sexual activity is inadvisable or contraindicated.^{110 143 152 154 164 165 167} Discontinue vasoactive therapy in patients who develop penile angulation, cavernosal fibrosis, or Peyronie’s disease during therapy.^{143 167}

Intracavernosal therapy (administered by self-injection) may be problematic in those receiving anticoagulants, who cannot tolerate transient hypotension, and those with poor manual dexterity, poor vision, or severe psychiatric disease.¹³⁰

Priapism Associated with Intracavernosal Injection

Consider possibility of persistent priapism (a medical emergency) associated with intracavernosal injection; may require immediate medical and/or surgical intervention.^{103 105 106 107 108 110 113 115 116 120 122 125 127 129 130 131 132 137 178 181 a} (See Advice to Patients.)

The risk of priapism can be reduced by careful patient instruction and dosage titration.^{132 137 142}

Management of priapism includes aspiration of cavernosal blood^{105 110 113 115 116 120 127 129} and/or intracavernous injection of an α-adrenergic agonist (e.g., metaraminol, phenylephrine) or dopamine.^{103 105 106 107 108 109 110 111 113 115 120 127 129 137 179} Rarely, more radical therapy for priapism (e.g., cavernospongiosus or Winter’s shunt) may be necessary,^{104 105 106 110 129 179} such as in patients with persistent priapism (e.g., longer than 24 hours).^{104 110}

Sensitivity Reactions

Hepatic Hypersensitivity

Hepatic hypersensitivity with GI symptoms, jaundice, eosinophilia, and altered hepatic function tests results reported.^{180 181 a}

If such hypersensitivity occurs, discontinue the drug.^{180 181 a}

General Precautions

Adequate Patient Monitoring

Administer papaverine injection only under the supervision of qualified clinician.^{181 a}

Glaucoma

Use with caution in patients with glaucoma.^{180 181 a}

Abuse and Dependence

Potential abuse and dependence to papaverine reported.^{181 a}

Specific Populations

Pregnancy

Category C.¹⁸¹

Lactation

Not known whether papaverine distributes into human milk.^{181 a} Use with caution in nursing women.^{181 a}

Pediatric Use

Safety and efficacy of papaverine in pediatric patients not established.^{181 a}

However, children have received papaverine hydrochloride dosages of 6 mg/kg daily, divided into 4 IM or IV doses.^a

Common Adverse Effects

Following oral administration: Nausea,^a abdominal distress,^{180 a} anorexia,^{180 a} constipation,^{180 a} malaise,^{180 a} drowsiness,^a vertigo,^{180 a} sweating,^{180 a} headache,^{180 a} diarrhea,^{180 a} rash,^{180 a} flushing of the face,^{180 a} increased heart rate,^{180 a} increased depth of respirations,^{180 a} slight increase in BP,^{180 a} sedation.^{181 a}

Following IV administration: General discomfort,¹⁸¹ nausea,¹⁸¹ abdominal discomfort,¹⁸¹ anorexia,¹⁸¹ constipation,¹⁸¹ diarrhea,¹⁸¹ skin rash,¹⁸¹ malaise,¹⁸¹ headache,¹⁸¹ flushing,¹⁸¹ sweating,¹⁸¹ sedation,¹⁸¹ hepatitis,¹⁸¹ hypotension,¹⁸¹ hypertension,¹⁸¹ thrombosis at IV injection site.^a

Following intracavernosal administration: Priapism,^{103 105 106 107 108 110 113 115 116 120 122 125 127 129 130 131 132 137 178} transient pain,^{105 108 110 129} referred glans pain,^{108 110 129} burning,¹⁰³ paresthesia.^{105 110 129}

Interactions for Papaverine Hydrochloride

Specific Drugs

Drug	Interaction	Comments
CNS depressants	Possible increased papaverine effects a
Levodopa	Papaverine may block dopamine receptors and interfere with the therapeutic effects of levodopa a	Avoid concomitant use; do not use in patients with Parkinson's diseasea
Morphine	Possible synergisma

Papaverine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from GI tract.^a

Onset

Fairly rapid.^a

Following intracavernosal injection, erectile response usually occurs within 10 minutes.^{105 106 108 112 113 114 116 118 119 129 132}

Duration

Oral administration of extended-release capsules may provide continuous drug release over a 12-hour period.^a

Following intracavernosal injection, erectile response may persist for 1 to several hours.^{105 106 108 112 113 114 116 118 119 129 132}

Plasma Concentrations

Constant plasma concentrations can be maintained with oral administration at 6-hour intervals.^{181 a}

Distribution

Extent

Distributed throughout the body, with highest concentrations in fat deposits and liver.¹⁸¹

Not known if papaverine distributes into human milk.^{181 a}

Plasma Protein Binding

90%.^{181 a}

Elimination

Metabolism

Rapidly metabolized in the liver.^{181 a}

Elimination Route

Excreted in urine,^{181 a} principally as inactive metabolites.¹⁸¹

Stability

Storage

Oral

Capsules

15–30°C.^{180 a} Protect from moisture.¹⁸⁰

Parenteral

Injection

15–30°C.^{181 a} Protect from light; keep in the original carton until time of use.¹⁸¹

Compatibility

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

Parenteral

Solution Incompatibility

Do not add papaverine hydrochloride injection to lactated Ringer’s injection because a precipitate would result.^{181 a}

ActionsActions

• 
  

  Main therapeutic action is a direct spasmolytic effect on smooth muscles.^{180 181 a}

  
  


• 
  

  Spasmolytic effect most pronounced on blood vessels including the coronary, cerebral, pulmonary, and peripheral arteries; also relaxes smooth muscles of the bronchi, GI tract, ureters, and biliary system.^{180 181 a}

  
  


• 
  

  Relaxes cardiac muscle by directly depressing the excitability of the myocardium, prolonging the refractory period, and depressing conduction.^{180 181 a}

  
  


• 
  

  In the presence of vascular occlusion, may act by overcoming reflex vasoconstriction in collateral vessels.^a

  
  


• 
  

  Direct vasodilating action on cerebral blood vessels may explain benefit reported in cerebral vascular encephalopathy.¹⁸⁰

  
  


• 
  

  Minimal CNS actions;^{180 a} although large doses may have a depressant effect.^{181 a}

  
  


• 
  

  Weak calcium-channel activity with high doses.^{181 a}

  
  


• 
  

  Little, if any, analgesic action.^a

  
  

Advice to Patients

• 
  

  Advise patients receiving the drug via intracavernosal injection of potential for prolonged erections (priapism) and steps to take in the event that this serious adverse effect occurs.^{132 142 178 179}

  
  


• 
  

  Importance of seeking immediate medical attention if an erection persists >4 hours or is extremely painful.^{132 142}

  
  


• 
  

  Instruct patients receiving the drug via intracavernosal injection to visit their clinician regularly (e.g., at 3-month intervals) to assess therapeutic benefit, including the need for possible dosage adjustment, and of potential adverse effects associated with such therapy.^{143 147 159 167}

  
  


• 
  

  Importance of informing clinicians if risk factors for cardiovascular disease are present prior to initiating any treatment.^a

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{180 181}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{180 181}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{180 181} (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

Papaverine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Bulk	Powder
Oral	Capsules, extended-release	150 mg*	Papaverine Hydrochloride Capsules ER	Sandoz
			Para-Time SR	Time-Cap
Parenteral	Injection	30 mg/mL*	Papaverine Hydrochloride Injection (with chlorobutanol 0.5% in multiple-dose vials or preservative-free in single-dose vials)	American Regent, Bedford

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 2008. 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

100. Tu YH, Allen LV Jr, Wang DP. Stability of papaverine hydrochloride and phentolamine mesylate in injectable mixtures. Am J Hosp Pharm. 1987; 44:2524-7. [PubMed 2446497]

101. Romankiewicz JA, McManus J, Gotz VP et al. Medications not to be refrigerated. Am J Hosp Pharm. 1979; 36:1541-5. [PubMed 517543]

102. Stillwell S (Eli Lilly and Company, Indianapolis, IN): Personal communication; 1986 Sept 10.

103. Sidi AA, Cameron JS, Duffy LM et al. Intracavernous drug-induced erections in the management of male erectile dysfunction: experience with 100 patients. J Urol. 1986; 135:704-6. [IDIS 214073] [PubMed 2421014]

104. Lindoro J, Castro JC, Cruz F et al. Treatment of priapism. Lancet. 1984; 2:1348. [PubMed 6150362]

105. Anon. Intracavernous injections for impotence. Med Lett Drugs Ther. 1987; 29:95-6. [PubMed 3670212]

106. Robinette MA, Moffat MJ. Intracorporal injection of papaverine and phentolamine in the management of impotence. Br J Urol. 1986; 58:692-5. [PubMed 3801830]

107. Ellis LR, Nellans RE, Kramer-Levien DJ et al. Evaluation of the first 300 patients treated at an outpatient center for male sexual dysfunction. West J Med. 1987; 147:296-300. [IDIS 233499] [PubMed 3673062]

108. Nellans RE, Ellis LR, Kramer-Levien D. Pharmacological erection: diagnosis and treatment applications in 69 patients. J Urol. 1987; 138:52-4. [IDIS 232011] [PubMed 2439712]

109. Fernandez JA, Basha MA, Wilson GC. Emergency treatment of papaverine priapism. J Emerg Med. 1987; 5:289-91. [PubMed 3624835]

110. Lue TF, Tanagho EA. Physiology of erection and pharmacological management of impotence. J Urol. 1987; 137:829-36. [IDIS 229174] [PubMed 3553617]

111. Mizutani M, Nakano H, Sagami K et al. Treatment of post-traumatic priapism by intracavernous injection of α-stimulant. Urol Int. 1986; 41:312-4. [PubMed 3787856]

112. Sidi Ami, Cameron JS, Dykstra DD et al. Vasoactive intracavernous pharmacotherapy for the treatment of erectile impotence in men with spinal cord injury. J Urol. 1987; 138:539-42. [IDIS 234478] [PubMed 2442418]

113. Gasser TC, Roach RM, Larsen EH et al. Intracavernous self-injection with phentolamine and papaverine for the treatment of impotence. J Urol. 1987; 137:678-80. [IDIS 227800] [PubMed 3550149]

114. Larsen EH, Gasser TC, Bruskewitz RC. Fibrosis of corpus cavernosum after intracavernous injection of phentolamine/papaverine. J Urol. 1987; 137:292-3. [IDIS 225679] [PubMed 3806824]

115. Trapp JD. Pharmacologic erection program for the treatment of male impotence. South Med J. 1987; 60:426-7.

116. Zorgniotti AW, Lefleur RS. Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J Urol. 1985; 133:39-41. [PubMed 2578067]

117. Juenemann KP, Lue TF, Fournier GR Jr et al. Hemodynamics of papaverine- and phentolamine-induced penile erection. J Urol. 1986; 136:158-61. [PubMed 3712604]

118. Wyndaele JJ, de Meyer JM, de Sy WA et al. Intracavernous injection of vasoactive drugs, an alternative for treating impotence in spinal cord injury patients. Paraplegia. 1986; 24:271-5. [PubMed 3774363]

119. Al-Juburi AZ, O’Donnell PD. Penile self-injection for impotence in patients after radical cystectomy-ileal loop. Urology. 1987; 30:29-30. [PubMed 3603906]

120. Kiely EA, Williams G, Goldie L. Assessment of the immediate and long-term effects of pharmacologically induced penile erections in the treatment of psychogenic and organic impotence. Br J Urol. 1987; 59:164-9. [PubMed 3828713]

121. Puyau FA, Lewis RW, Balkin P et al. Dynamic corpus cavernosography: effect of papaverine injection. Radiology. 1987; 164:179-82. [IDIS 232219] [PubMed 3588901]

122. Brindley GS. Maintenance treatment of erectile impotence by cavernosal unstriated muscle relaxant injection. Br J Psychiatry. 1986; 149:210-5. [PubMed 3640652]

123. Turini D, Barbanti G, Beneforti P et al. Intracavernous therapy in impotence after pelvic trauma: a preliminary study. Eur Urol. 1986; 12:413-7. [PubMed 3816897]

124. Virag R, Frydman D, Legman M et al. Intracavernous injection of papaverine as a diagnostic and therapeutic method in erectile failure. Angiology. 1984; 35:79-87. [PubMed 6696289]

125. Halsted DS, Weigel JW, Noble MJ et al. Papaverine-induced priapism: 2 case reports. J Urol. 1986; 136:109-10. [IDIS 217940] [PubMed 3712593]

126. Zorgniotti AW. Corpus cavernosum blockade for impotence: practical aspects and results in 250 cases. J Urol. 1986; 135:306A.

127. van Driel MF, de Vries AI, Mensink HJA. Intracavernous self-injection of papaverine in the treatment of erectile impotence after major surgery. J Enterostom Ther. 1987; 14:101-4.

128. Williams G. Impotence: treatment by autoinjection of vasoactive drugs. BMJ. 1987; 295:1279. [IDIS 235999] [PubMed 3120975]

129. Anon. Intracavernous injections for impotence. Med Lett Drugs Ther. 1990; 32:116-7. [PubMed 2255296]

130. NIH Consensus Development Panel on Impotence. JAMA. 1993; 270:83-90.

131. Anon. Vasodilators provide new therapy for erectile dysfunction. F-D-C Rep. 1992; 54:16-7.

132. Krane RJ, Goldstein I, Saenz de Tejada I. Impotence. N Engl J Med. 1989; 321:1648-59. [PubMed 2685600]

133. Eli Lilly and Company. Papaverine hydrochloride injection prescribing information. Indianapolis, IN; 1994 Oct.

134. Lilly Research Laboratories, Indianapolis, IN: Personal commumnication; 1994 Dec.

135. Eli Lilly and Company, Indianapolis, IN: Personal communication; 1994 Dec.

136. Eli Lilly and Company, Indianapolis, IN: Personal communication; 1994 Aug.

137. Kirby RS. Impotence: diagnosis and management of male erectile dysfunction. BMJ. 1994; 308:957-61. [IDIS 328981] [PubMed 8173405]

138. Bennett AH, Carpenter AJ, Barada JH. An Improved vasoactive drug combination for a pharmacological erection program. J Urol. 1991; 146:1564-5. [IDIS 296354] [PubMed 1719248]

139. Montorsi F, Guazzoni G, Bergamaschi F et al. Four-drug intracavernous therapy for impotence due to corporeal veno-occlusive dysfunction. J Urol. 1993; 149:1291-5. [IDIS 313863] [PubMed 7683061]

140. Montorsi F, Guazzoni G, Bergamaschi F et al. Effectiveness and safety of multidrug intracavernous therapy for vasculogenic impotence. Urology. 1993; 42:554-8. [PubMed 7694416]

141. von Heyden B, Donatuucci CF, Kaula N et al. Intracavernous pharmacotherapy for impotence: selection of appropriate agent and dose. J Urol. 1993; 149:1288-90. [IDIS 313862] [PubMed 8479018]

142. Reviewers’ comments (personal observations).

143. The Upjohn Company. Caverject (alprostadil) injection for intracavernosal use prescribing information. Kalamazoo, MI; 1995 Jul.

144. Linet OI, Ogrinc FG. Dose-escalating study with maintenance phase using alprostadil (prostaglandin E1, PGE1) sterile powder in patients with erectile dysfunction. Technical Report No. 9124-93-006. The Upjohn Company: Kalamazoo, MI; 1993 Dec 3.

145. Linet OI, Ogrinc FG. Long-term safety study with alprostadil sterile powder (alprostadil S.Po.; prostaglandin E₁, PGE₁) in patients with erectile dysfunction. Technical Report No. 9124-93-007. The Upjohn Company: Kalamazoo, MI; 1993 Dec 10.

146. Linet OI, Ogrinc FG. Dose- escalating study with maintenance phase using alprostadil (prostaglandin E₁, PGE₁) sterile powder (S.Po.) in elderly patients with erectile dysfunction. Technical Report No. 9124- 95-002. The Upjohn Company: Kalamazoo, MI; 1995 Jan 17.

147. Linet OI. Clinical pharmacology of alprostadil. In: Goldstein I, Lue TF, eds. The role of alprostadil in the diagnosis and treatment of erectile dysfunction. Princeton: Excerpta Medica; 1993:28-39.

148. Ishii N, Watanabe H, Irisawa C et al. Intracavernous injection of prostaglandin E1 for the treatment of erectile impotence. J Urol. 1989; 141:323-5. [IDIS 251538] [PubMed 2913354]

149. Allen RP, Engel RM, Smolev JK et al. Objective double-blind evaluation of erectile function with intracorporeal papaverine in combination with phentolamine and/or prostaglandin E1. J Urol. 1992; 148:1181-3. [IDIS 303448] [PubMed 1404632]

150. Godschalk MF, Chen J, Katz PG et al. Treatment of erectile failure with prostaglandin E1: a double-blind, placebo-controlled, dose-response study. J Urol. 1994; 151:1530-2. [IDIS 329635] [PubMed 8189563]

151. Chen J, Godschalk M, Katz PG et al. The lowest effective dose of prostaglandin E1 as treatment for erectile dysfunction. J Urol. 1995; 153:80-1. [IDIS 340107] [PubMed 7966797]

152. Godschalk MF, Chen J, Katz PG et al. Prostaglandin E1 as treatment for erectile failure in elderly men. J Am Geriatr Soc. 1994; 42:1263-5. [IDIS 339613] [PubMed 7983289]

153. Porst H. Prostaglandin E1 and the nitric oxide donor linsidomine for erectile failure: a diagnostic comparative study of 40 patients. J Urol. 1993; 149:1280-3. [IDIS 313861] [PubMed 8479015]

154. The Upjohn Company, Kalamazoo, MI: Personal communication.

155. Porst H. Prostaglandin E₁ in male impotence—its diagnostic and therapeutic use in 2000 patients. Int J Impotence Res. 1992; 4(Suppl 2):A88.

156. Whitehead ED. Impotence: should primary care physicians give penile injections? Geriatrics. 1995; 50:14. Letter. (IDIS 341817)

157. Gerber GS, Levine LA. Pharmacological erection program using prostaglandin E1. J Urol. 1991; 146:786-9. [IDIS 287641] [PubMed 1875494]

158. Artoux MJ, McQueen KD. Alprostadil in impotence. DICE. 1991; 25:363-6.

159. Linet OI, Neff LL. Intracavernous prostaglandin E1 in erectile dysfunction. Clin Investig. 1994; 72:139-49. [PubMed 8186662]

160. Ravnik-Oblak M, Oblak C, Vodusek DB et al. Intracavernous injection of prostaglandin E₁ in impotent diabetic men. Int J Impotence Res. 1990; 2:143-49.

161. Hirsch IH, Bagley DH, Christinzio J. Dosage considerations in the self-administration of PGE-1 for erectile dysfunction. J Urol. 1990; 143(Suppl):305A.

162. Montorsi F, Guazzoni G, Bergamaschi F et al. Clinical reliability of multi-drug intracavernous vasoactive pharmacotherapy for diabetic impotence. Acta Diabetol. 1994; 31:1-5. [PubMed 8043890]

163. Whitehead ED, Klyde BJ, Zussman S et al. Treatment alternatives for impotence. Postgrad Med. 1990; 88:139-52. [IDIS 269901] [PubMed 2199954]

164. Hwang TIS, Yang CR, Wang SJ et al. Impotence evaluated by the use of prostaglandin E1. J Urol. 1989; 141:1357-9. [IDIS 255242] [PubMed 2724434]

165. von Heyden B, Donatucci CF, Marshall GA et al. A prostaglandin E1 dose-response study in man. J Urol. 1993; 150:1825-8. [IDIS 321902] [PubMed 8230515]

166. Murray FT, Geisser M, Murphy TC. Evaluation and treatment of erectile dysfunction. Am J Med Sci. 1995; 309:99-109. [IDIS 342934] [PubMed 7847449]

167. Bénard F, Lue TF. Self-administration in the pharmacological treatment of impotence. Drugs. 1990; 39:394-8. [PubMed 2184008]

168. Duffy LM, Sidi AA, Lange PH. Vasoactive intracavernous pharmacotherapy—the nursing role in teaching self-injection therapy. J Urol. 1987; 138:1198-200. [IDIS 247278] [PubMed 3669166]

169. Montague DK. Editorial: treatment of erectile dysfunction. J Urol. 1993; 150:1833. [IDIS 321904] [PubMed 8230516]

170. Goldstein I, Lue TF, Padma-Nathan H et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998; 338:1397-404. [IDIS 405966] [PubMed 9580646]

171. Goldstein I, Rosen RC, Steers WD. Sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998; 339:701-2.

172. Standing Medical Advisory Committee, United Kingdom Department of Health. The use of sildenafil in the treatment of erectile dysfunction. London; November 9,1998. From the United Kingdom Department of Health Web Site ().

173. Lipshultz LI, Kim ED. Treatment of erectile dysfunction in men with diabetes. JAMA. 1999; 281:465-6. [IDIS 418627] [PubMed 9952210]

174. Pfizer Inc, New York, NY: Personal communication on sildenafil.

175. Reviewers’ comments (personal observations) on sildenafil.

176. The Process of Care Consensus Panel. Position paper: the process of care model for evaluation and treatment of erectile dysfunction. Int J Impotence Res. 1999; 11:59-70.

177. Sarramon JP. Editorial comments on the process of care model for evaluation and treatment of erectile dysfunction. Int J Impotence Res. 1999; 11:73.

178. Erectile Dysfunction Guideline Update Panel, American Urological Association Education and Research. Management of erectile dysfunction: An update. 2005. Available at (. Accessed 2005 Oct. 20.

179. Erectile Dysfunction Guideline Update Panel, American Urological Association Education and Research. Priapism: Guideline on the management of priapism. 2003. Available at (. Accessed 2005 Oct. 20.

180. Eon Labs. Papaverine hydrochloride sustained release capsules prescribing information. Laurelton, NY; 2005 Mar.

181. American Regent, Inc. Papaverine hydrochloride injection prescribing information. Shirley, NY; 2003 Jan.

182. Sandoz Corporation. Princeton, NJ: Personal communication.

183. United Research. Philadelphia, PA: Personal communication.

184. American Regent. Shirley, NY: Personal communication.

a. AHFS drug information 2007. McEvoy GK, ed. Papaverine. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1796–8.

More Papaverine Hydrochloride resources

• Papaverine Hydrochloride Side Effects (in more detail)
• Papaverine Hydrochloride Use in Pregnancy & Breastfeeding
• Drug Images
• Papaverine Hydrochloride Drug Interactions
• P