Medicone Ointment

Pronunciation: BEN-zoe-kane
Generic Name: Benzocaine
Brand Name: Americaine

Medicone Ointment is used for:

Temporarily relieving pain, burning, and itching caused by hemorrhoids or other rectal conditions.

Medicone Ointment is a topical anesthetic. It works by numbing the skin.

Do NOT use Medicone Ointment if:

• you are allergic to any ingredient in Medicone Ointment

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

Before using Medicone Ointment:

Some medical conditions may interact with Medicone Ointment. 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 diabetes, peripheral vascular problems, or skin irritation

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

This may not be a complete list of all interactions that may occur. Ask your health care provider if Medicone Ointment 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 Medicone Ointment:

Use Medicone Ointment as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Medicone Ointment is for external use around the outside of the rectum only. Do not use Medicone Ointment inside the rectum.


• Cleanse area with mild soap and warm water when possible and rinse thoroughly. Gently dry by patting or blotting with tissue or a soft cloth. Apply to affected area as instructed.


• If your symptoms do not improve within 7 days, stop using Medicone Ointment and contact your doctor.


• If you miss a dose of Medicone Ointment, use it as soon as you remember. Continue to use it as directed by your doctor or on the package label.

Ask your health care provider any questions you may have about how to use Medicone Ointment.

Important safety information:

• If you notice any new symptoms or your symptoms get worse, contact your doctor.


• If ointment contacts clothing or fabrics, wash in warm water only. Do not bleach.

Possible side effects of Medicone Ointment:

All medicines may cause side effects, but many people have no, or minor, side effects. When used in small doses, no COMMON side effects have been reported with this product. 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); rectal bleeding, redness, irritation, swelling, or pain.

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: Medicone 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. Medicone Ointment may be harmful if swallowed.

Proper storage of Medicone Ointment:

Store Medicone Ointment between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Medicone Ointment out of the reach of children and away from pets.

General information:

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


• Medicone Ointment 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 Medicone Ointment. 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 Medicone resources

• Medicone Side Effects (in more detail)
• Medicone Use in Pregnancy & Breastfeeding
• Medicone Support Group
• 0 Reviews · Be the first to review/rate this drug

Tarceva

Generic Name: erlotinib hydrochloride

Dosage Form: tablets
FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

Non-Small Cell Lung Cancer (NSCLC)

Tarceva monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen [see Clinical Studies (14.1)].

Results from two, multicenter, placebo-controlled, randomized, Phase 3 trials conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of Tarceva with platinum-based chemotherapy [carboplatin and paclitaxel or gemcitabine and cisplatin] and its use is not recommended in that setting [see Clinical Studies (14.3)].

Pancreatic Cancer

Tarceva in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer [see Clinical Studies (14.3)].

2. DOSAGE AND ADMINISTRATION

Recommended Dose - NSCLC

The recommended daily dose of Tarceva for non-small cell lung cancer is 150 mg taken at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs. There is no evidence that treatment beyond progression is beneficial.

Recommended Dose - Pancreatic Cancer

The recommended daily dose of Tarceva for pancreatic cancer is 100 mg taken at least one hour before or two hours after the ingestion of food, in combination with gemcitabine (see the gemcitabine package insert). Treatment should continue until disease progression or unacceptable toxicity occurs.

Dose Modifications

In patients who develop an acute onset of new or progressive pulmonary symptoms, such as dyspnea, cough or fever, treatment with Tarceva should be interrupted pending diagnostic evaluation. If Interstitial Lung Disease (ILD) is diagnosed, Tarceva should be discontinued and appropriate treatment instituted as necessary [see Warnings and Precautions (5.1)].

Diarrhea can usually be managed with loperamide. Patients with severe diarrhea who are unresponsive to loperamide or who become dehydrated may require dose reduction or temporary interruption of therapy. Patients with severe skin reactions may also require dose reduction or temporary interruption of therapy.

When dose reduction is necessary, the Tarceva dose should be reduced in 50 mg decrements.

In patients who are taking Tarceva with a strong CYP3A4 inhibitor such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice, a dose reduction should be considered if severe adverse reactions occur. Similarly, in patients who are taking Tarceva with an inhibitor of both CYP3A4 and CYP1A2 like ciprofloxacin, a dose reduction of Tarceva should be considered if severe adverse reactions occur. [see Drug Interactions (7)].

Pre-treatment with the CYP3A4 inducer rifampicin decreased erlotinib AUC by about 2/3 to 4/5. Use of alternative treatments lacking CYP3A4 inducing activity is strongly recommended. If an alternative treatment is unavailable, an increase in the dose of Tarceva should be considered as tolerated at two week intervals while monitoring the patient’s safety. The maximum dose of Tarceva studied in combination with rifampicin is 450 mg. If the Tarceva dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. John's Wort. These too should be avoided if possible [see Drug Interactions (7)].

Cigarette smoking has been shown to reduce erlotinib exposure. Patients should be advised to stop smoking. If a patient continues to smoke, a cautious increase in the dose of Tarceva, not exceeding 300 mg may be considered, while monitoring the patient’s safety. However, efficacy and long-term safety (> 14 days) of a dose higher than the recommended starting doses have not been established in patients who continue to smoke cigarettes. If the Tarceva dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking [see Clinical Pharmacology (12.3)].

Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B), patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with Tarceva [see WARNINGS and PRECAUTIONS (5.2 )]. Treatment with Tarceva should be used with extra caution in patients with total bilirubin > 3 x ULN.   Tarceva dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range. In the setting of worsening liver function tests, before they become severe, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. Tarceva dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Warnings and Precautions (5.2 , 5.3 ), Adverse Reactions (6.3) and Use in Specific Populations (8.6 )]. 

3. DOSAGE FORMS AND STRENGTHS

25 mg tablets

White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in orange with a “T” and “25” on one side and plain on the other side.

100 mg tablets

White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in gray with “T” and “100” on one side and plain on the other side.

150 mg tablets

White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in maroon with “T” and “150” on one side and plain on the other side.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

Pulmonary Toxicity

There have been infrequent reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving Tarceva for treatment of NSCLC, pancreatic cancer or other advanced solid tumors. In the randomized single-agent NSCLC study [see CLINICAL STUDIES (14.1)], the incidence of ILD-like events (0.8%) was the same in both the placebo and Tarceva groups. In the pancreatic cancer study - in combination with gemcitabine –  [see Clinical Studies (14.3)], the incidence of ILD-like events was 2.5% in the Tarceva plus gemcitabine group vs. 0.4% in the placebo plus gemcitabine group.

The overall incidence of ILD-like events in approximately 4900 Tarceva-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) was approximately 0.7%. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome and lung infiltration. Symptoms started from 5 days to more than 9 months (median 39 days) after initiating Tarceva therapy. In the lung cancer trials most of the cases were associated with confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections.

In the event of an acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, Tarceva therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, Tarceva should be discontinued and appropriate treatment instituted as needed [see Dosage and Administration (2.3 )].

Patients with Hepatic Impairment

In a pharmacokinetic study in patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 out of 15 patients died on treatment or within 30 days of the last Tarceva dose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining 8 patients died from progressive disease. Six out of the 10 patients who died had baseline total bilirubin > 3 x ULN suggesting severe hepatic impairment. Treatment with Tarceva should be used with extra caution in patients with total bilirubin > 3 x ULN. Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with Tarceva. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3 )].

Hepatotoxicity 

Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of Tarceva, particularly in patients with baseline hepatic impairment. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is recommended. In the setting of worsening liver function tests, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. Tarceva dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Adverse Reactions (6.3) and Dosage and Administration (2.3 )].

Renal Failure

Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia or concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (eg, pre-existing renal disease, medical conditions or medications that may lead to renal disease, or other predisposing conditions including advanced age), Tarceva therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration [see Adverse Reactions (6.3) and Dosage and Administration (2.3 )].

Myocardial infarction/ischemia

In the pancreatic carcinoma trial, six patients (incidence of 2.3%) in the Tarceva/gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.2%) and one died due to myocardial infarction.

Cerebrovascular accident

In the pancreatic carcinoma trial, six patients in the Tarceva/gemcitabine group developed cerebrovascular accidents (incidence: 2.3%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents.

Microangiopathic Hemolytic Anemia with Thrombocytopenia

In the pancreatic carcinoma trial, two patients in the Tarceva/gemcitabine group developed microangiopathic hemolytic anemia with thrombocytopenia (incidence: 0.8%). Both patients received Tarceva and gemcitabine concurrently. In comparison, in the placebo/gemcitabine group there were no cases of microangiopathic hemolytic anemia with thrombocytopenia.

Use in Pregnancy

Pregnancy Category D

Women of childbearing potential should avoid becoming pregnant while being treated with Tarceva. Erlotinib administered to rabbits during organogenesis at doses that result in plasma drug concentrations of approximately 3 times those in humans (AUCs at 150 mg daily dose) was associated with embryo/fetal lethality and abortion. When erlotinib was administered to female rats prior to mating and through the first week of pregnancy, at doses 0.3 or 0.7 times the clinical dose of 150 mg, on a mg/m2 basis, there was an increase in early resorptions that resulted in a decrease in the number of live fetuses. [see Use in Specific Populations (8.1)]

Elevated International Normalized Ratio and Potential Bleeding

International Normalized Ratio (INR) elevations and infrequent reports of bleeding events including gastrointestinal and non-gastrointestinal bleedings have been reported in clinical studies, some associated with concomitant warfarin administration. Patients taking warfarin or other coumarin-derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR. [see Adverse Reactions (6.3)].

6. ADVERSE REACTIONS

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

Safety evaluation of Tarceva is based on 856 cancer patients who received Tarceva as monotherapy, 308 patients who received Tarceva 100 or 150 mg plus gemcitabine, and 1228 patients who received Tarceva concurrently with other chemotherapies.

There have been reports of serious events, including fatalities, in patients receiving Tarceva for treatment of NSCLC, pancreatic cancer or other advanced solid tumors [see Warnings and Precautions (5) and Dosage and Administration (2.3 )].

Non-Small Cell Lung Cancer

Adverse events, regardless of causality, that occurred in at least 10% of patients treated with single-agent Tarceva at 150 mg and at least 3% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.0) Grade in Table 1.

The most common adverse reactions in patients receiving single-agent Tarceva 150 mg were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%, respectively, in Tarceva-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of Tarceva-treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days. 

Table 1: Adverse Reactions Occurring More Frequently (≥ 3%) in the Single Agent Tarceva Group than in the Placebo Group and in ≥10% of Patients in the Tarceva Group.

	Tarceva 150 mg N = 485			Placebo N = 242
NCI-CTC Grade	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
MedDRA Preferred Term	%	%	%	%	%	%
Rash	75	8	<1	17	0	0
Diarrhea	54	6	<1	18	<1	0
Anorexia	52	8	1	38	5	<1
Fatigue	52	14	4	45	16	4
Dyspnea	41	17	11	35	15	11
Cough	33	4	0	29	2	0
Nausea	33	3	0	24	2	0
Infection	24	4	0	15	2	0
Vomiting	23	2	<1	19	2	0
Stomatitis	17	<1	0	3	0	0
Pruritus	13	<1	0	5	0	0
Dry skin	12	0	0	4	0	0
Conjunctivitis	12	<1	0	2	<1	0
Keratoconjunctivitis sicca	12	0	0	3	0	0
Abdominal pain	11	2	<1	7	1	<1

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent Tarceva 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 (>2.5 – 5.0 x ULN) ALT elevations occurred in 4% and <1% of Tarceva and placebo treated patients, respectively. Grade 3 (>5.0 – 20.0 x ULN) elevations were not observed in Tarceva-treated patients. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe. [see Dosage and Administration (2.3)]

Pancreatic Cancer

Adverse events, regardless of causality, that occurred in at least 10% of patients treated with Tarceva 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer are summarized by NCI-CTC (version 2.0) Grade in Table 2.

The most common adverse reactions in pancreatic cancer patients receiving Tarceva 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the Tarceva plus gemcitabine arm, Grade 3/4 rash and diarrhea were each reported in 5% of Tarceva plus gemcitabine-treated patients. The median time to onset of rash and diarrhea was 10 days and 15 days, respectively. Rash and diarrhea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving Tarceva plus gemcitabine. The 150 mg cohort was associated with a higher rate of certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption. 

Table 2: Adverse Reactions Occurring in ≥ 10% of Tarceva-treated Pancreatic Cancer Patients: 100 mg cohort

*Includes all MedDRA preferred terms in the Infections and Infestations System Organ Class
	Tarceva + Gemcitabine 1000 mg/m2 IV N=259			Placebo + Gemcitabine 1000 mg/m2 IV N=256
NCI-CTC Grade	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
MedDRA Preferred Term	%	%	%	%	%	%
Fatigue	73	14	2	70	13	2
Rash	69	5	0	30	1	0
Nausea	60	7	0	58	7	0
Anorexia	52	6	<1	52	5	<1
Diarrhea	48	5	<1	36	2	0
Abdominal pain	46	9	<1	45	12	<1
Vomiting	42	7	<1	41	4	<1
Weight decreased	39	2	0	29	<1	0
Infection*	39	13	3	30	9	2
Edema	37	3	<1	36	2	<1
Pyrexia	36	3	0	30	4	0
Constipation	31	3	1	34	5	1
Bone pain	25	4	<1	23	2	0
Dyspnea	24	5	<1	23	5	0
Stomatitis	22	<1	0	12	0	0
Myalgia	21	1	0	20	<1	0
Depression	19	2	0	14	<1	0
Dyspepsia	17	<1	0	13	<1	0
Cough	16	0	0	11	0	0
Dizziness	15	<1	0	13	0	<1
Headache	15	<1	0	10	0	0
Insomnia	15	<1	0	16	<1	0
Alopecia	14	0	0	11	0	0
Anxiety	13	1	0	11	<1	0
Neuropathy	13	1	<1	10	<1	0
Flatulence	13	0	0	9	<1	0
Rigors	12	0	0	9	0	0

In the pancreatic carcinoma trial, 10 patients in the Tarceva/gemcitabine group developed deep venous thrombosis (incidence: 3.9%). In comparison, 3 patients in the placebo/gemcitabine group developed deep venous thrombosis (incidence 1.2%). The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis, was similar in the two treatment arms: 11% for Tarceva plus gemcitabine and 9% for placebo plus gemcitabine.

No differences in Grade 3 or Grade 4 hematologic laboratory toxicities were detected between the Tarceva plus gemcitabine group compared to the placebo plus gemcitabine group.

Severe adverse events (≥grade 3 NCI-CTC) in the Tarceva plus gemcitabine group with incidences < 5% included syncope, arrhythmias, ileus, pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial infarction/ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency [see Warnings and Precautions (5)].

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) have been observed following the administration of Tarceva plus gemcitabine in patients with pancreatic cancer. Table 3 displays the most severe NCI-CTC grade of liver function abnormalities that developed. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.3)].

Table 3: Liver Function Test Abnormalities (most severe NCI-CTC grade) in Pancreatic Cancer Patients: 100 mg Cohort

	Tarceva + Gemcitabine 1000 mg/m2 IV N = 259			Placebo + Gemcitabine 1000 mg/m2 IV N = 256
NCI-CTC Grade	Grade 2	Grade 3	Grade 4	Grade 2	Grade 3	Grade 4
Bilirubin	17 %	10%	<1%	11%	10%	3%
ALT	31%	13%	<1%	22%	9%	0%
AST	24%	10%	<1%	19%	9%	0%

NSCLC and Pancreatic Cancer Indications

During the NSCLC and the combination pancreatic cancer trials, infrequent cases of gastrointestinal bleeding have been reported, some associated with concomitant warfarin or NSAID administration. [see Warnings and Precautions (5.9)]. These adverse events were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis. Cases of acute renal failure or renal insufficiency, including fatalities, with or without hypokalemia have been reported. [see Warnings and Precautions (5.4)].  Cases of Grade 1 epistaxis were also reported in both the single-agent NSCLC and the pancreatic cancer clinical trials.

NCI-CTC Grade 3 conjunctivitis and keratitis have been reported infrequently in patients receiving Tarceva therapy in the NSCLC and pancreatic cancer clinical trials. Corneal ulcerations may also occur. [see Patient Counseling Information (17)].

 Hair and nail disorders including alopecia, hirsutism, eyelash/eyebrow changes, paronychia and brittle and loose nails have been reported in clinical trials and during post-marketing use of Tarceva.

In patients who develop skin rash, the appearance of the rash is typically erythematous and maculopapular and it may resemble acne with follicular pustules, but is histopathologically different. This skin reaction commonly occurs on the face, upper chest and back, but may be more generalized or severe (NCI-CTC Grade 3 or 4) with desquamation. Associated symptoms may include itching, tenderness and/or burning. Dry skin with or without digital skin fissures may occur.

Hepatic failure has been reported in patients treated with single-agent Tarceva or Tarceva combined with chemotherapy in clinical studies and during post-marketing use of Tarceva [see Warnings and Precautions (5.3 )]; it is not possible to reliably estimate the frequency or establish a causal relationship to Tarceva treatment.

In general, no notable differences in the safety of Tarceva monotherapy or in combination with gemcitabine could be discerned between females or males and between patients younger or older than the age of 65 years [see Use in Specific Populations (8.4)]. The safety of Tarceva appears similar in Caucasian and Asian patients.

7. DRUG INTERACTIONS

Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increases erlotinib AUC by 2/3. When Tarceva was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration [Cmax] increased by 39% and 17% respectively. Caution should be used when administering or taking Tarceva with ketoconazole and other strong CYP3A4 inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole and grapefruit or grapefruit juice. [see Dosage and Administration (2.3 )].

Pre-treatment with the CYP3A4 inducer rifampicin for 7 days prior to Tarceva decreased erlotinib AUC by about 2/3 to 4/5, which is equivalent to a dose of about 30 to 50 mg in NSCLC patients. In a separate study, treatment with rifampicin for 11 days, with co-administration of a single 450 mg dose of Tarceva on day 8 resulted in a mean erlotinib exposure (AUC) that was 57.6% of that observed following a single 150 mg Tarceva dose in the absence of rifampicin treatment [see Dose Modifications (2.3

Nadolol and Bendroflumethiazide

Nadolol and Bendroflumethiazide Description

Nadolol and Bendroflumethiazide tablets, USP for oral administration combines two antihypertensive agents: nadolol, a nonselective beta-adrenergic blocking agent, and bendroflumethiazide, a thiazide diuretic-antihypertensive. Formulations: 40 mg and 80 mg nadolol per tablet combined with 5 mg bendroflumethiazide. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10 aluminum lake, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium lauryl sulfate.

Nadolol

Nadolol, USP is a white to off-white crystalline powder. It is freely soluble in alcohol and in methanol; soluble in water at pH 2; slightly soluble in chloroform, in methylene chloride, in isopropyl alcohol, and in water (between pH 7 and pH 10), insoluble in acetone, in benzene, in ether, in hexane, and in trichloroethane.

Nadolol is designated chemically as 1-(tert-butylamino)-3-{(5,6,7,8-tetrahydro-cis-6,7-dihydroxy-1-naphthyl)oxy}-2-propanol. It has the molecular formula of C17H27NO4 and molecular weight of 309.40. The structural formula is shown below.

Bendroflumethiazide

Bendroflumethiazide, USP is a white to cream colored, finely divided, crystalline powder. It is practically insoluble in water, freely soluble in alcohol and in acetone.

Bendroflumethiazide is designated chemically as + 3-benzyl-3,4-dihydro-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It has a molecular formula of C15H14F3N3O4S2 and a molecular weight of 421.42. The structural formula is shown below.

Nadolol and Bendroflumethiazide - Clinical Pharmacology

Nadolol

Nadolol is a nonselective beta-adrenergic receptor blocking agent. Clinical pharmacology studies have demonstrated beta-blocking activity by showing (1) reduction in heart rate and cardiac output at rest and on exercise, (2) reduction of systolic and diastolic blood pressure at rest and on exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.

Nadolol specifically competes with beta-adrenergic receptor agonists for available beta receptor sites; it inhibits both the beta1 receptors located chiefly in cardiac muscle and the beta2 receptors located chiefly in the bronchial and vascular musculature, inhibiting the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation proportionately. Nadolol has no intrinsic sympathomimetic activity and, unlike some other beta-adrenergic blocking agents, nadolol has little direct myocardial depressant activity and does not have an anesthetic-like membrane-stabilizing action. Animal and human studies show that nadolol slows the sinus rate and depresses AV conduction. In dogs, only minimal amounts of nadolol were detected in the brain relative to amounts in blood and other organs and tissues. Nadolol has low lipophilicity as determined by octanol/water partition coefficient, a characteristic of certain beta-blocking agents that has been correlated with the limited extent to which these agents cross the blood-brain barrier, their low concentration in the brain, and low incidence of CNS-related side effects.

In controlled clinical studies, nadolol at doses of 40 to 320 mg/day has been shown to decrease both standing and supine blood pressure, the effect persisting for approximately 24 hours after dosing.

The mechanism of the antihypertensive effects of beta-adrenergic receptor blocking agents has not been established; however, factors that may be involved include (1) competitive antagonism of catecholamines at peripheral (non-CNS) adrenergic neuron sites (especially cardiac) leading to decreased cardiac output, (2) a central effect leading to reduced tonic-sympathetic nerve outflow to the periphery, and (3) suppression of renin secretion by blockade of the beta-adrenergic receptors responsible for renin release from the kidneys.

While cardiac output and arterial pressure are reduced by nadolol therapy, renal hemodynamics are stable, with preservation of renal blood flow and glomerular filtration rate.

By blocking catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure, nadolol generally reduces the oxygen requirements of the heart at any given level of effort, making it useful for many patients in the long-term management of angina pectoris. On the other hand, nadolol can increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure.

Although beta-adrenergic receptor blockade is useful in treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen AV block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.

Absorption of nadolol after oral dosing is variable, averaging about 30 percent. Peak serum concentrations of nadolol usually occur in 3 to 4 hours after oral administration and the presence of food in the gastrointestinal tract does not affect the rate or extent of nadolol absorption. Approximately 30 percent of the nadolol present in serum is reversibly bound to plasma protein.

Unlike many other beta-adrenergic blocking agents, nadolol is not metabolized by the liver and is excreted unchanged, principally by the kidneys.

The half-life of therapeutic doses of nadolol is about 20 to 24 hours, permitting once-daily dosage. Because nadolol is excreted predominantly in the urine, its half-life increases in renal failure (see PRECAUTIONS: General, and DOSAGE AND ADMINISTRATION). Steady-state serum concentrations of nadolol are attained in 6 to 9 days with once-daily dosage in persons with normal renal function. Because of variable absorption and different individual responsiveness, the proper dosage must be determined by titration.

Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.

Bendroflumethiazide

The mechanism of action of bendroflumethiazide results in an interference with the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic potency.

Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and bicarbonate.

The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.

Onset of action of thiazides occurs in 2 hours and the peak effect at about 4 hours. Duration of action persists for approximately 6 to 12 hours. Thiazides are eliminated rapidly by the kidney.

Indications and Usage for Nadolol and Bendroflumethiazide

Nadolol and Bendroflumethiazide tablets are indicated in the management of hypertension.

This fixed combination drug is not indicated for initial therapy of hypertension. If the fixed combination represents the dose titrated to the individual patient’s needs, it may be more convenient than the separate components.

Contraindications

Nadolol

Nadolol is contraindicated in bronchial asthma, sinus bradycardia and greater than first degree conduction block, cardiogenic shock, and overt cardiac failure (see WARNINGS).

Bendroflumethiazide

Bendroflumethiazide is contraindicated in anuria. It is also contraindicated in patients who have previously demonstrated hypersensitivity to bendroflumethiazide or other sulfonamide-derived drugs.

Warnings

Nadolol

Cardiac Failure

Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta-blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, they can be used with caution in patients with a history of failure who are well compensated, usually with digitalis and diuretics. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.

IN PATIENTS WITHOUT A HISTORY OF HEART FAILURE, continued use of beta-blockers can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of heart failure, the patient should be digitalized and/or treated with diuretics, and the response observed closely, or nadolol should be discontinued (gradually, if possible).

Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal:  Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction has occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered nadolol, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 to 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, nadolol administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue nadolol therapy abruptly even in patients treated only for hypertension.

Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema)

PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS. Nadolol should be administered with caution since it may block bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta2 receptors.

Major Surgery

Because beta-blockade impairs the ability of the heart to respond to reflex stimuli and may increase the risks of general anesthesia and surgical procedures, resulting in protracted hypotension or low cardiac output, it has generally been suggested that such therapy should be withdrawn several days prior to surgery. Recognition of the increased sensitivity to catecholamines of patients recently withdrawn from beta-blocker therapy, however, has made this recommendation controversial. If possible, beta-blockers should be withdrawn well before surgery takes place. In the event of emergency surgery, the anesthesiologist should be informed that the patient is on beta-blocker therapy. The effects of nadolol can be reversed by administration of beta-receptor agonists such as isoproterenol, dopamine, dobutamine, or norepinephrine. Difficulty in restarting and maintaining the heart beat has also been reported with beta-adrenergic receptor blocking agents.

Diabetes and Hypoglycemia

Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia and blood pressure changes) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of antidiabetic drugs.

Thyrotoxicosis

Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blockade which might precipitate a thyroid storm.

Bendroflumethiazide

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

Lithium generally should not be given with diuretics; diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such concomitant therapy.

Precautions

General

Nadolol

Nadolol should be used with caution in patients with impaired renal function (see DOSAGE AND ADMINISTRATION).

Bendroflumethiazide

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, namely: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance may include: dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances, such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis or when severe cirrhosis is present.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Concurrent administration of a potassium-sparing diuretic or potassium supplements may be indicated in these patients.

Any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Latent diabetes mellitus may become manifest during thiazide administration.

The antihypertensive effect of thiazide diuretics may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident, as indicated by a rising nonprotein nitrogen or blood urea nitrogen (BUN), a careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing diuretic therapy.

Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Information for Patients

Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of therapy without the physician’s advice. Although cardiac failure rarely occurs in properly selected patients, patients being treated with beta-adrenergic blocking agents should be advised to consult the physician at the first sign or symptom of impending failure.

The patient should also be advised of a proper course in the event of an inadvertently missed dose.

The patient should be informed of symptoms that would suggest potential adverse effects and told to report them promptly.

Laboratory Tests

Serum electrolyte levels should be regularly monitored (see WARNINGS: Bendroflumethiazide , also PRECAUTIONS: General: Bendroflumethiazide).

Drug Interactions

Nadolol

When administered concurrently the following drugs may interact with beta-adrenergic receptor blocking agents:

Anesthetics: General: Exaggeration of the hypotension induced by general anesthetics (see WARNINGS: Nadolol: Major Surgery).

Antidiabetic Drugs (Oral Agents and Insulin): Hypoglycemia or hyperglycemia; adjust dosage of antidiabetic drug accordingly (see WARNINGS: Nadolol: Diabetes and Hypoglycemia).

Catecholamine-Depleting Drugs (e.g., Reserpine): Additive effect; monitor closely for evidence of hypotension and/or excessive bradycardia (e.g., vertigo, syncope, postural hypotension).

Response to Treatment for Anaphylactic Reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

Bendroflumethiazide

When administered concurrently the following drugs may interact with thiazide diuretics:

Alcohol, Barbiturates, or Narcotics: Potentiation of orthostatic hypotension may occur.

Amphotericin B, Corticosteroids, or Corticotropin (ACTH): May intensify electrolyte imbalance, particularly hypokalemia. Monitor potassium levels; use potassium replacements if necessary.

Anticoagulants (Oral): Dosage adjustments of anticoagulant medication may be necessary since bendroflumethiazide may decrease their effects.

Antigout Medications: Dosage adjustments of antigout medication may be necessary since bendroflumethiazide may raise the level of blood uric acid.

Other Antihypertensive Medications (e.g., Ganglionic or Peripheral Adrenergic Blocking Agents): Dosage adjustments may be necessary since bendroflumethiazide may potentiate their effects.

Antidiabetic Drugs (Oral Agents and Insulin): Since thiazides may elevate blood glucose levels, dosage adjustments of antidiabetic agents may be necessary.

Calcium Salts: Increased serum calcium levels due to decreased excretion may occur. If calcium must be prescribed monitor serum calcium levels and adjust calcium dosage accordingly.

Cardiac Glycosides: Enhanced possibility of digitalis toxicity associated with hypokalemia. Monitor potassium levels; use potassium replacement if necessary.

Cholestyramine Resin and Colestipol HCl: May delay or decrease absorption of bendroflumethiazide. Sulfonamide diuretics should be taken at least one hour before or 4 to 6 hours after these medications.

Diazoxide: Enhanced hyperglycemic, hyperuricemic, and antihypertensive effects. Be cognizant of possible interaction; monitor blood glucose and serum uric acid levels.

Lithium Salts: May enhance lithium toxicity due to reduced renal clearance. Avoid concurrent use; if lithium must be prescribed monitor serum lithium levels and adjust lithium dosage accordingly. (See WARNINGS.)

MAO Inhibitors: Dosage adjustments of one or both agents may be necessary since hypotensive effects are enhanced.

Nondepolarizing Muscle Relaxants, Preanesthetics and Anesthetics Used in Surgery (e.g., Tubocurarine Chloride and Gallamine Triethiodide): Effects of these agents may be potentiated; dosage adjustments may be required. Monitor and correct any fluid and electrolyte imbalances prior to surgery if feasible.

Nonsteroidal Anti-Inflammatory Agents: In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing or thiazide diuretics. Therefore, when bendroflumethiazide and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Methenamine: Possible decreased effectiveness due to alkalinization of the urine.

Pressor Amines (e.g., Norepinephrine): Decreased arterial responsiveness, but not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Use caution in patients taking both medications who undergo surgery. Administer preanesthetic and anesthetic agents in reduced dosage, and if possible, discontinue bendroflumethiazide one week prior to surgery.

Probenecid or Sulfinpyrazone: Increased dosage of these agents may be necessary since bendroflumethiazide may have hyperuricemic effects.

Drug/Laboratory Test Interactions

Bendroflumethiazide may produce false-negative results with the phentolamine and tyramine tests; may interfere with the phenolsulfonphthalein test due to decreased excretion; and it may cause diagnostic interference of serum electrolyte levels, blood and urine glucose levels, and a decrease in serum PBI levels without signs of thyroid disturbance.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Nadolol

In chronic oral toxicologic studies (1 to 2 years) in mice, rats, and dogs, nadolol did not produce any significant toxic effects. In two-year oral carcinogenicity studies in rats and mice, nadolol did not produce any neoplastic, preneoplastic, or nonneoplastic pathologic lesions. In fertility and general reproductive performance studies in rats, nadolol caused no adverse effect.

Bendroflumethiazide

Studies have not been performed to evaluate carcinogenic potential, mutagenesis, or whether this drug adversely affects fertility in males or females.

Pregnancy

Teratogenic effects

Nadolol

Category C

In animal reproduction studies with nadolol, evidence of embryo- and fetotoxicity was found in rabbits, but not in rats or hamsters, at doses 5 to 10 times greater (on a mg/kg basis) than the maximum indicated human dose. No teratogenic potential was observed in any of these species.

There are no adequate and well controlled studies in pregnant women. Nadolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates whose mothers are receiving nadolol at parturition have exhibited bradycardia, hypoglycemia, and associated symptoms.

Bendroflumethiazide

Category C

Animal reproduction studies have not been conducted with bendroflumethiazide. It is also not known whether this drug can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Bendroflumethiazide should be given to a pregnant woman only if clearly needed.

Nonteratogenic effects

Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.

Nursing Mothers

Both Nadolol and Bendroflumethiazide are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from both drugs, a decision should be made whether to discontinue nursing or to discontinue therapy taking into account the importance of Nadolol and Bendroflumethiazide tablets to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Nadolol and Bendroflumethiazide tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reaction to this drug may be greater in patients with impaired function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions

Nadolol

Most adverse effects have been mild and transient and have rarely required withdrawal of therapy.

Cardiovascular: Bradycardia with heart rates of less than 60 beats per minute occurs commonly, and heart rates below 40 beats per minute and/or symptomatic bradycardia were seen in about 2 of 100 patients. Symptoms of peripheral vascular insufficiency, usually of the Raynaud type, have occurred in approximately 2 of 100 patients. Cardiac failure, hypotension, and rhythm/conduction disturbances have each occurred in about 1 of 100 patients. Single instances of first degree and third degree heart block have been reported; intensification of AV block is a known effect of beta-blockers (see also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Central Nervous System: Dizziness or fatigue has been reported in approximately 2 of 100 patients; paresthesias, sedation, and change in behavior have each been reported in approximately 6 of 1,000 patients.

Respiratory: Bronchospasm has been reported in approximately 1 of 1,000 patients (see CONTRAINDICATIONS and WARNINGS).

Gastrointestinal: Nausea, diarrhea, abdominal discomfort, constipation, vomiting, indigestion, anorexia, bloating, and flatulence have been reported in 1 to 5 of 1,000 patients.

Miscellaneous: Each of the following has been reported in 1 to 5 of 1,000 patients: rash; pruritus; headache; dry mouth, eyes, or skin; impotence or decreased libido; facial swelling; weight gain; slurred speech; cough; nasal stuffiness; sweating; tinnitus; blurred vision. Reversible alopecia has been reported infrequently.

The following adverse reactions have been reported in patients taking nadolol and/or other beta-adrenergic blocking agents, but no causal relationship to nadolol has been established.

Central Nervous System: Reversible mental depression progressing to catatonia; visual disturbances; hallucinations; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability with slightly clouded sensorium, and decreased performance on neuropsychometrics.

Gastrointestinal: Mesenteric arterial thrombosis; ischemic colitis; elevated liver enzymes.

Hematologic: Agranulocytosis; thrombocytopenic or nonthrombocytopenic purpura.

Allergic: Fever combined with aching and sore throat; laryngospasm; respiratory distress.

Miscellaneous: Pemphigoid rash; hypertensive reaction in patients with pheochromocytoma; sleep disturbances; Peyronie’s disease.

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with nadolol.

Bendroflumethiazide

Gastrointestinal: Nausea, vomiting, cramping and anorexia are not uncommon; diarrhea, constipation, gastric irritation, abdominal bloating, jaundice (intrahepatic cholestatic jaundice), hepatitis, and sialadenitis occasionally occur; and pancreatitis has been reported.

Central Nervous System: Dizziness, vertigo, paresthesia, headache, and xanthopsia occasionally occur.

Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, and aplastic anemia have been reported.

Dermatologic-Hypersensitivity: Purpura, exfoliative dermatitis, pruritus, ecchymosis, urticaria, necrotizing angiitis (vasculitis, cutaneous vasculitis), respiratory distress including pneumonitis, fever, and anaphylactic reactions occasionally occur; photosensitivity and rash have been reported.

Cardiovascular: Orthostatic hypotension may occur and may be potentiated by coadministration with certain other drugs (e.g., alcohol, barbiturates, narcotics, other antihypertensive medications, etc.; see PRECAUTIONS: Drug Interactions).

Other: Muscle spasm, weakness, or restlessness is not uncommon; hyperglycemia, glycosuria, metabolic acidosis in diabetic patients, hyperuricemia, allergic glomerulonephritis, and transient blurred vision occasionally occur.

Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.

Overdosage

In the event of overdosage, nadolol may cause excessive bradycardia, cardiac failure, hypotension, or bronchospasm.

In addition to the expected diuresis, overdosage of bendroflumethiazide may produce varying degrees of lethargy which may progress to coma with minimal depression of respiration and cardiovascular function and without significant serum electrolyte changes or dehydration. The mechanism of thiazide-induced CNS depression is unknown. Gastrointestinal irritation may occur. Transitory increase in BUN has been reported, and serum electrolyte changes may occur, especially in patients with impaired renal function.

Treatment

Nadolol can be removed from the general circulation by hemodialysis. In determining the duration of corrective therapy, note must be taken of the long duration of the effect of nadolol. In addition to gastric lavage, the following measures should be employed, as appropriate.

Excessive Bradycardia

Administer atropine (0.25 to 1 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.

Cardiac Failure

Administer a digitalis glycoside and diuretic. It has been reported that glucagon may also be useful in this situation.

Hypotension

Administer vasopressors, e.g., epinephrine or norepinephrine. (There is evidence that epinephrine may be the drug of choice.)

Bronchospasm

Administer a beta2-stimulating agent and/or a theophylline derivative.

Stupor or Coma

Supportive therapy as warranted.

Gastrointestinal Effects

Symptomatic treatment as needed.

BUN and/or Serum Electrolyte Abnormalities

Institute supportive measures as required to maintain hydration, electrolyte balance, respiration, and cardiovascular and renal function.

Nadolol and Bendroflumethiazide Dosage and Administration

DOSAGE MUST BE INDIVIDUALIZED (SEE INDICATIONS). Nadolol and Bendroflumethiazide TABLETS MAY BE ADMINISTERED WITHOUT REGARD TO MEALS.

Bendroflumethiazide is usually given at a dose of 5 mg daily. The usual initial dose of nadolol is 40 mg once daily whether used alone or in combination with a diuretic. Bendroflumethiazide in Nadolol and Bendroflumethiazide tablets is 30 percent more bioavailable than that of 5 mg bendroflumethiazide tablets. Conversion from 5 mg bendroflumethiazide tablets to Nadolol and Bendroflumethiazide tablets represents a 30 percent increase in dose of bendroflumethiazide. The initial dose of Nadolol and Bendroflumethiazide tablets may therefore be the 40 mg/5 mg tablet once daily. When the antihypertensive response is not satisfactory, the dose may be increased by administering the 80 mg/5 mg tablet once daily.

When necessary, another antihypertensive agent may be added gradually beginning with 50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure.

Dosage Adjustment in Renal Failure

Absorbed nadolol is excreted principally by the kidneys and, although nonrenal elimination does occur, dosage adjustments are necessary in patients with renal impairment. The following dose intervals are recommended:

Creatinine Clearence (mL/min/1.73 m2)	Dosage Interval (hours)
> 50	24
31 to 50	24 to 36
10 to 30	24 to 48
< 10	40 to 60

How is Nadolol and Bendroflumethiazide Supplied

Nadolol and Bendroflumethiazide Tablets, USP are available in strengths of 40 mg/5 mg and 80 mg/5 mg.

The 40 mg nadolol combined with 5 mg bendroflumethiazide tablet is a yellow, round, scored tablet debossed with M above the score and 96 below the score on one side of the tablet and blank on the other side.

NDC 0378-0096-01

bottles of 100 tablets

NDC 0378-0096-05

bottles of 500 tablets

The 80 mg nadolol combined with 5 mg bendroflumethiazide tablet is a yellow, round, scored tablet debossed with M above the score and 99 below the score on one side of the tablet and blank on the other side.

NDC 0378-0099-01

bottles of 100 tablets

NDC 0378-0099-05

bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]

Avoid excessive heat.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

JULY 2007

NDBF:R1

 

PRINCIPAL DISPLAY PANEL - 40 mg/ 5 mg

NDC 0378-0096-01

NADOLOL and

BENDROFLUMETHIAZIDE

TABLETS, USP

40 mg/5 mg

100 TABLETS (Rx only)

Each tablet contains:

Nadolol, USP 40 mg

Bendroflumethiazide, USP 5 mg

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication out

of the reach of children.

Store at 20° to 25°C (68° to 77°F ).

[See USP for Controlled Room

Temperature.]

Avoid excessive heat.

Usual Dosage: See accompanying

prescribing information.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

RM0096A

 

PRINCIPAL DISPLAY PANEL - 80 mg/ 5 mg

NDC 0378-0099-01

NADOLOL and

BENDROFLUMETHIAZIDE

TABLETS, USP

80 mg/5 mg

100 TABLETS (Rx only)

Each tablet contains:

Nadolol, USP 80 mg

Bendroflumethiazide, USP 5 mg

Dispense in a tight, light-resistant

container as defined in the USP

using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication out

of the reach of children.

Store at 20° to 25°C (68° to 77°F ).

[See USP for Controlled Room

Temperature.]

Avoid excessive heat.

Usual Dosage: See accompanying

prescribing information.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

RM0099A

Nadolol and Bendroflumethiazide  Nadolol and Bendroflumethiazide  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0378-0096 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength NADOLOL (NADOLOL) NADOLOL 40 mg BENDROFLUMETHIAZIDE (BENDROFLUMETHIAZIDE) BENDROFLUMETHIAZIDE 5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   CROSCARMELLOSE SODIUM   D&C YELLOW NO. 10   MAGNESIUM STEARATE   CELLULOSE, MICROCRYSTALLINE   STARCH, CORN   SODIUM LAURYL SULFATE

Product Characteristics Color YELLOW Score 2 pieces Shape ROUND Size 7mm Flavor Imprint Code M;96 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0378-0096-01 100 TABLET In 1 BOTTLE, PLASTIC None 2 0378-0096-05 500 TABLET In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA078688	05/13/2011

Nadolol and Bendroflumethiazide  Nadolol and Bendroflumethiazide  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0378-0099 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength NADOLOL (NADOLOL) NADOLOL 80 mg BENDROFLUMETHIAZIDE (BENDROFLUMETHIAZIDE) BENDROFLUMETHIAZIDE 5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   CROSCARMELLOSE SODIUM   D&C YELLOW NO. 10   MAGNESIUM STEARATE   CELLULOSE, MICROCRYSTALLINE   STARCH, CORN   SODIUM LAURYL SULFATE