Droxil may be available in the countries listed below.
Cefadroxil is reported as an ingredient of Droxil in the following countries:
Cefadroxil monohydrate (a derivative of Cefadroxil) is reported as an ingredient of Droxil in the following countries:
International Drug Name Search
Plisil may be available in the countries listed below.
Paroxetine is reported as an ingredient of Plisil in the following countries:
International Drug Name Search
nye-kar-di-peen
In the U.S.
Available Dosage Forms:
Therapeutic Class: Cardiovascular Agent
Pharmacologic Class: Calcium Channel Blocker
Chemical Class: Dihydropyridine
Nicardipine is used alone or together with other medicines to treat severe chest pain (angina) or high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled .
Nicardipine is a calcium channel blocker. It works by affecting the movement of calcium into the cells of the heart and blood vessels. As a result, nicardipine relaxes blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload .
nicardipine is available only with your doctor's prescription .
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For nicardipine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to nicardipine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies have not been performed on the relationship of age to the effects of nicardipine in the pediatric population. Safety and efficacy have not been established .
Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of nicardipine in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems which may require an adjustment of dose in patients receiving nicardipine .
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking nicardipine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using nicardipine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
Using nicardipine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Using nicardipine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
The presence of other medical problems may affect the use of nicardipine. Make sure you tell your doctor if you have any other medical problems, especially:
In addition to the use of nicardipine, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium. Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet .
Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well .
Remember that nicardipine will not cure your high blood pressure, but it does help control it. You must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease .
The dose of nicardipine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of nicardipine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of nicardipine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
It is very important that your doctor check your progress at regular visits to make sure nicardipine is working properly and to check for unwanted effects .
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Get emergency help immediately if any of the following symptoms of overdose occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: nicardipine side effects (in more detail)
The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.
The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.
DRUG FACTS ACTIVE INGREDIENT 1.1 % NEUTRAL SODIUM FLUORIDE
For prevention of tooth decay, orthodontic decalcification and hypersensitivity.
As with all medications, keep out of reach of children.
NeutraMaxxtm 5000 with Tri-Calcium Phosphate is a self applied dentifrice for prevention of tooth decay, orthodontic decalcification and hypersensitivity
Warnings Do not swallow For topical use only
This prescription dentifrice is recommended for adults and pediatric patients 6 years and older
Apply a thin ribbon of NeutraMaxxtm 5000 TCP along the length of the toothbrush no more than "pea size" total dose. Brush for two minutes.
After brushing ADULTS - Expectorate, do not eat for 30 minutes. CHILDREN 6 YEARS OF AGE OR OLDER - Expectorate and rinse mouth with water. Use at bedtime in place of your regular toothpaste or as directed by your dental professional.
Inactive Ingredients: Deionized Water, Sorbitol, Hydrated Silica, PEG, Carboxymethylcellulose, Xylitol, MonoSodium Phosphate, Titanium Dioxide, Mint Flavor, Sodium Saccharin, Tri-Calcium Phosphate
Call 1-479-787-5168 M-F 9am to 5 pm CST
REFRESHING MINT FLAVOR RELIEVES SENSITIVITY
ANTI-CAVITY TOOTHPASTE NeutraMaxx tm 5000 TCP XYLITO1.1% Neutral Sodium Fluoride 5000 ppm Sweetened with Xylitol
DOES NOT CONTAIN SODIUM LAURYL SULFATE RX ONLY Net wt. 4 oz (112 G)
Manufactured By: MASSCO DENTAL A Division of Dunagin Pharmaceuticals, Gravette, AR (479) 787-5168 www.masscodental.net
| NEUTRAMAXX 5000 TCP sodium fluoride paste, dentifrice | ||||||||||||||||||||||||
| ||||||||||||||||||||||||
| ||||||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| OTC monograph final | part355 | 08/01/2011 | |
| Labeler - Massco Dental A Division of Dunacin Pharmaceuticals (008081858) |
| Registrant - Massco Dental A Division of Dunacin Pharmaceuticals (008081858) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Massco Dental A Division of Dunacin Pharmaceuticals | 008081858 | manufacture | |
Blowfly may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Clofenvinfos is reported as an ingredient of Blowfly in the following countries:
Cypermethrin is reported as an ingredient of Blowfly in the following countries:
International Drug Name Search
Generic Name: galsulfase (Intravenous route)
gal-SUL-fase
In the U.S.
Available Dosage Forms:
Therapeutic Class: Endocrine-Metabolic Agent
Pharmacologic Class: Enzyme
Galsulfase injection is used to treat symptoms of an inherited disease called mucopolysaccharidosis (MPS VI) disease or Maroteaux-Lamy syndrome. This medicine improves walking and stair-climbing ability in patients who are lacking a certain enzyme called N-acetylgalactosamine 4-sulfatase in the body.
This medicine is to be given only by or under the direct supervision of a doctor.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of galsulfase injection in children 5 years of age and older. Your doctor may choose to use this medication in children under the age of 5 at their discretion.
Appropriate studies have not been performed on the relationship of age to the effects of galsulfase injection in the geriatric population. Safety and efficacy have not been established.
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | B | Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus. |
There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
A nurse or other trained health professional will give you or your child this medicine in a hospital. This medicine is given through a needle placed in one of your veins.
The usual dose schedule for this medicine is one time each week. This medicine must be given slowly, so the needle will remain in place for at least 4 hours.
You or your child may also receive medicines to help prevent possible allergic reactions to the injection.
If you will be taking this medicine for a long time, it is very important that your doctor check you or your child at regular visits for any problems or unwanted effects that may be caused by this medicine.
This medicine may cause serious types of allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor or nurse right away if you have dizziness; lightheadedness; a rash; itching; hoarseness; trouble with breathing or swallowing; or any swelling of your hands, face, or mouth while you or your child are using this medicine.
This medicine may cause headaches and skin reactions, such as a rash or itching, while you are receiving the injection or within 24 hours after you receive it. Check with your doctor or nurse right away if you or your child have any of these symptoms.
This medicine can cause fever and allergic-type reactions. You or your child will receive medicines to prevent these side effects, and that medicine may make you drowsy. Avoid driving, using machines, or doing anything else that could be dangerous if you are not alert.
Your doctor may want you or your child to join a patient registry for patients using this medicine. This will help you monitor the progress of your disease while on long-term treatment using this medicine.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor or nurse immediately if any of the following side effects occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: Naglazyme side effects (in more detail)
The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.
The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.
Class: Dihydropyridines
VA Class: CV200
CAS Number: 21829-25-4
Brands: Adalat, Adalat CC, Nifedical XL, Procardia XL, Procardia
Calcium-channel blocking agent; dihydropyridine derivative.284 307 342 343
Used in the management of Prinzmetal variant angina and chronic stable angina pectoris.a
Calcium channel blockers considered the drugs of choice in management of Prinzmetal variant angina.a
Appears to be as effective as β-adrenergic blocking agents (e.g., propranolol) and/or oral nitrates in the management of chronic stable angina pectoris; however, generally should be used only when the patient cannot tolerate adequate doses of or is refractory to these drugs.a
Management of hypertension (alone or in combination with other classes of antihypertensive agents).126 141 237 309 342 343 344 345 348 350 351
Only extended-release formulations currently are recommended for management of hypertension.121 126 141 178 181 183 184 191 192 193 197 201 202 204 205 206 207 208 209 210 211 212 213 225 226 237 264 309 342 344 348 350 (See Cautions.)
One of several preferred initial therapies in hypertensive patients with a high risk of developing CAD, including those with diabetes mellitus.383
Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.383
Not recommended for management of hypertensive crises.283 284 295 307 338 339 340 341 350 383
As an alternative to IV hydralazine, short-acting (conventional, immediate-release) nifedipine is included by JNC 7 for management of acute severe hypertension in pregnant women with preeclampsia† when delivery is imminent.393 However, JNC 7 acknowledges that this use is controversial.393
Drug of choice for the management of Raynaud’s phenomenon†,144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 296 297 298 305 306 preferably administered as extended-release formulations.296 297 305 306
Current ACOG guidelines for management of preterm labor state that there is no clear first-line tocolytic agent;389 analysis of pooled data from randomized, controlled studies suggests calcium channel blockers (principally nifedipine) may be more effective than, and preferable to, other agents (e.g., magnesium sulfate, β-adrenergic agonists).390
Administer capsules orally 3 times daily.284
Swallow capsules whole.284
Administer orally once daily.126 342
Extended-release tablets should be swallowed intact and should not be chewed, crushed, or broken.126 342
Manufacturer recommends that Adalat CC be administered on an empty stomach.342
The shell of the extended-release tablet does not dissolve and may be passed in the stool.342 343
Whenever extended-release tablets are dispensed or administered, care should be taken to ensure that the extended-release dosage form actually was prescribed.126
Dosage of extended-release nifedipine tablets should be decreased gradually with close clinical supervision when discontinuance of the drug is required.126 342
Manufacturer states that two 30-mg Adalat CC extended-release tablets may be interchanged with one 60-mg Adalat CC extended-release tablet; however, three 30-mg Adalat CC extended-release tablets should not be considered interchangeable with one 90-mg Adalat CC extended-release tablet.342
Initially, 0.25–0.5 mg/kg daily given in 1 dose or 2 divided doses.395 Increase dosage as necessary up to a maximum dosage of 3 mg/kg (up to 120 mg) daily, given in 1 dose or 2 divided doses.395
Initially, 10 mg 3 times daily.284 307
Increase dosage gradually at 7- to 14-day intervals until optimum control of angina is obtained.a
May increase more rapidly to 90 mg daily in increments of 30 mg daily over a 3-day period if symptoms so warrant and patient’s tolerance and response to therapy are frequently assessed.284 307
In hospitalized patients who are closely monitored, dosage may be increased in 10-mg increments at 4- to 6-hour intervals, as necessary to control pain and arrhythmias caused by ischemia.284 307 Single doses usually should not exceed 30 mg.284 307
Usual maintenance dosage is 10–20 mg 3 times daily.a In some patients, especially those with evidence of coronary artery spasm, increased dosages of 20–30 mg 3 or 4 times daily and rarely, more than 120 mg daily may be necessary.a
Initially, 30 or 60 mg once daily.126
Increase dosage gradually at 7- to 14-day intervals until optimum control of angina is obtained.a
Dosage may be increased more rapidly to 90 mg daily in increments of 30 mg daily after steady state is achieved (usually achieved on the second day of therapy with a given dose) if symptoms so warrant and patient’s tolerance and response are frequently assessed.126
In some patients, especially those with evidence of coronary artery spasm, higher dosages may be necessary.a However, experience with antianginal dosages exceeding 90 mg once daily as extended-release tablets is limited and should be employed with caution and only when clinically necessary.126
Extended-release tablets can be substituted for the conventional capsules at the nearest equivalent total daily dose.126
Not recommended for use in the management of hypertension242 284 307 344 345 350 because of concerns about potential cardiovascular risks.240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 266 284 307 344 345 346 347 348
Initially, 30 or 60 mg once daily.126 350
Increase dosage gradually at 7- to 14-day intervals until optimum control of BP is obtained.126 342 a
Dosage may be increased more rapidly, if symptoms so warrant and the patient’s tolerance and response to therapy are frequently assessed.126
Usual maintenance dosage is 30–60 mg once daily.342
Conventional capsules: 10 mg repeated at 20-minute intervals to a maximum total dosage of 30 mg.393 The drug should be used cautiously with magnesium sulfate since a precipitous drop in BP can occur.393
Extended-release tablets: Maximum 3 mg/kg (up to 120 mg) daily.395
Conventional liquid-filled capsules: Maximum 30 mg as a single dose.284 307 Maximum 180 mg daily.284
Extended-release tablets: Maximum 120 mg daily.126
Extended-release tablets: Maximum 90 mg (Adalat CC) or 120 mg (Procardia XL) once daily.126 342 350 However, JNC currently recommends a lower maximum dosage of 60 mg daily.383
Known hypersensitivity to nifedipine or any ingredient in the formulation.126 284 307 342 343
Risk of excessive, poorly tolerated hypotension in patients being treated for angina; usually occurs during initial dosage titration or subsequent upward titration and may be more likely in patients receiving concomitant β-adrenergic blocking agent.114 126 129 284 286 307 Carefully monitor BP, especially during therapy initiation, titration, or dosage increase.126 284 342 a
Conventional (immediate-release) nifedipine formulations generally are contraindicated in the routine management of AMI because of negative inotropic effects and reflex sympathetic activation, tachycardia, and hypotension associated with its use.242 284 307 352 391 Do not administer within first 1–2 weeks after MI and avoid in acute coronary syndrome when infarction may be imminent.284 307
Risk of profound hypotension, cerebrovascular ischemia or stroke, myocardial ischemia or infarction, and/or death with use of conventional preparations for management of hypertensive crises;119 283 284 288 295 300 302 303 304 307 308 similar effects reported in patients receiving such preparations for angina or pulmonary hypertension.283 286 287 310 Do not use short-acting preparations for acute BP reduction or for chronic hypertension management.284 307
Rarely, increased frequency, duration, and/or severity of angina or AMI, particularly in patients with severe obstructive CAD, upon initiation or dosage increase of calcium channel blockers.126 284 342
Possible increased angina in patients recently withdrawn from β-blockers after nifedipine initiation.126 284 342 Taper dosage of β-blockers before initiation of nifedipine.126 284 342 (See Interactions.)
Risk of CHF, especially in those receiving concomitant β-adrenergic blocking agents, particularly in patients with aortic stenosis.126 284 342
Rash, dermatitis (including exfoliative dermatitis), erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity reactions, pruritus, urticaria, allergic hepatitis, and angioedema, principally oropharyngeal edema and occasionally breathing difficulty, reported.126 284 342
Consider possibility of deterioration in left ventricular function, especially in patients with CHF, if peripheral edema develops.126 284 342
Use extended-release tablets with caution in patients with preexisting GI narrowing; obstruction may occur.126
Category C.126 284 342
Distributed into milk.165 342 Discontinue nursing or the drug.342
Safety and efficacy remain to be fully established in children;126 284 however, some experts have recommended dosages for hypertension based on current limited clinical experience.395
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.284 342 Select dosage with caution.284 342
Use Adalat CC extended-release nifedipine tablets with caution in patients with renal impairment due to the possibility of altered absorption of the drug.342
Dizziness, lightheadedness, giddiness, flushing, heat sensation, headache, tremor, nervousness, mood changes, weakness, fatigue, asthenia, muscle cramps, nausea, heartburn, peripheral edema, dyspnea, cough, wheezing, nasal congestion, sore throat.126 284 342
Metabolized by CYP isoenzymes, principally CYP3A.342 May inhibit CYP3A; does not appear to affect CYP2D6.342
Drug or Food | Interaction | Comments |
|---|---|---|
β-Adrenergic blocking agents | Increased risk of severe hypotension, exacerbation of angina, CHF, and arrhythmiaa | Monitor patient and adjust nifedipine dosage as needed;342 gradually reduce β-blocker dosage instead of abruptly withdrawing;126 284 342 a |
Acarbose | Possible loss of glycemic control342 | Monitor glucose concentrations and adjust nifedipine dosage as needed342 |
Alcohol | Increased nifedipine bioavailability236 | |
Anticoagulants (e.g., coumarins) | Possible increased PT126 284 342 | |
Antifungals, azoles (fluconazole, itraconazole, ketoconazole) | Possible increased plasma nifedipine concentrations342 | Monitor BP and adjust nifedipine dosage as needed342 |
Antiretroviral agents (HIV protease inhibitors [amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir], nonnucleoside reverse transcriptase inhibitors [delavirdine]) | Possible increased plasma nifedipine concentrations342 | Use concomitantly with caution; monitor patient carefully342 |
Antituberculosis agents (rifabutin, rifampin) | Possible decreased plasma nifedipine concentrations342 401 | Adjust nifedipine dosage as needed342 |
Benazepril | Possible attenuation of tachycardic effect of nifedipine342 | |
Candesartan | Pharmacokinetic interaction unlikely342 | |
Carbamazepine | Possible decreased plasma nifedipine concentrations342 | Adjust nifedipine dosage as needed342 |
Clopidogrel | Pharmacokinetic interaction unlikely342 | |
Digoxin | Increased serum digoxin concentration106 107 126 | Monitor serum digoxin concentrations when nifedipine therapy is initiated, discontinued, or dosage is adjusted in patients receiving digoxin108 126 284 307 342 Monitor for signs and symptoms of digoxin toxicity and reduce dosage if necessary101 106 126 284 307 |
Diltiazem | Possible increased plasma nifedipine concentrations342 399 | |
Dolasetron | Pharmacokinetic interaction unlikely342 | |
Erythromycin | Possible increased plasma nifedipine concentrations342 | Monitor BP and adjust nifedipine dosage as needed342 |
Fentanyl | Potential for severe hypotensiona | If patient’s condition permits, temporarily withhold nifedipine for at least 36 hours before surgery if use of high-dose fentanyl is contemplated126 284 342 |
Flecainide | Insufficient clinical experience to recommend concomitant use342 | |
Grapefruit juice | Increased nifedipine bioavailability284 311 314 323 324 342 371 372 373 | Avoid concomitant use;284 314 342 371 372 373 discontinue grapefruit juice consumption at least 3 days prior to initiating nifedipine therapy342 |
Histamine H2-receptor antagonists (cimetidine, ranitidine) | Decreased clearance and increased plasma nifedipine concentrations and AUC with concomitant cimetidine or (to lesser extent) ranitidine115 116 125 284 342 | Cautiously titrate nifedipine dosage in patients receiving cimetidine; may need to reduce nifedipine dosage in patients stabilized on the drug if cimetidine therapy is initiated115 125 284 342 |
Hypotensive agents (captopril, doxazosin, hydralazine, methyldopa) | Increased incidence of severe hypotensiona | Observe patient closely when nifedipine is added to existing antihypertensive regimen, especially during initial titration or upward adjustment of nifedipine dosage126 284 342 |
Irbesartan | Pharmacokinetic interaction unlikely342 | |
Metformin | Possible increased absorption of metformin342 | |
Nefazodone | Possible increased plasma nifedipine concentrations342 | Monitor BP and adjust nifedipine dosage as needed342 |
Omeprazole | Pharmacokinetic interaction unlikely342 | |
Pantoprazole | Pharmacokinetic interaction unlikely342 | |
Phenobarbital | Possible decreased plasma nifedipine concentrations342 | Adjust nifedipine dosage as needed342 |
Phenytoin | Possible decreased phenytoin metabolism;166 167 possible decreased plasma nifedipine concentrations342 | Monitor plasma phenytoin concentrations when nifedipine is initiated or discontinued;166 monitor BP and adjust nifedipine dosage as needed342 |
Quinidine | Possible increased plasma nifedipine concentrations;342 397 possible decreased serum quinidine concentrations284 307 332 333 334 335 336 337 396 397 | Monitor heart rate and adjust nifedipine dosage as needed;342 monitor serum quinidine concentrations whenever nifedipine is initiated or discontinued; adjust quinidine dosage accordingly333 334 335 336 337 |
Quinupristin and dalfopristin | Possible increased plasma nifedipine concentrations342 378 | Monitor BP and adjust nifedipine dosage as needed342 |
Sirolimus | Pharmacokinetic interaction unlikely342 | |
St. John’s wort | Possible decreased plasma nifedipine concentrations342 | Adjust nifedipine dosage as needed342 |
Tacrolimus | Possible increased plasma tacrolimus concentrations342 | Monitor tacrolimus blood concentrations and adjust tacrolimus dosage as needed342 |
Tirofiban | Pharmacokinetic interaction unlikely342 | |
Valproic acid | Possible increased plasma nifedipine concentrations342 | Monitor BP and adjust nifedipine dosage as needed342 |
Verapamil | Possible increased plasma nifedipine concentrations342 | Monitor BP and adjust nifedipine dosage as needed342 |
Following oral administration of conventional capsules, approximately 90% of a dose is absorbed with peak serum concentrations usually attained within 0.5–2 hours.a
Oral bioavailability of extended-release tablets is approximately 75–89% of that achieved with same doses as conventional capsules.126 130 342
Peak plasma concentrationsfor extended-release tablets are attained within about 2.5–6 hours.130 342
Food decreases the rate but not extent of absorption from conventional capsules.140
Food can increase the early rate of GI absorption of extended-release tablets but does not affect overall bioavailability.126 342
Bioavailability is increased in patients with liver cirrhosis126 132 133 284 307 342 and may be particularly increased in those with portacaval shunts.132
Following oral administration of extended-release tablets (Adalat CC), , absorption of nifedipine may be altered in patients with renal impairment.342
Substantial reductions in GI retention time for prolonged periods (e.g., in patients with short-bowel syndrome) can result in decreased absorption from extended-release tablets.126
Increased mean peak plasma concentrations and average plasma concentrations compared with those in younger adults have been reported in healthy subjects >60 years of age receiving Adalat CC extended-release tablets.342
Nifedipine is distributed into milk.165
Approximately 92–98%.126 284
Plasma protein binding may be decreased in patients with renal126 133 139 284 307 342 or hepatic126 132 133 284 307 342 impairment.
Extensively metabolized in the liver by CYP isoenzymes, including CYP3A, to highly water soluble, inactive metabolites.126 284 342 a
Metabolites excreted in urine (60–80%) and feces (possibly via biliary elimination).126 342 a
2 hours (conventional capsules); 7 hours (Adalat CC extended-release tablets).126 284 342 a
Elimination may be altered in patients with hepatic impairment.126 132 133 284 307 342 Elimination half-life of 7 hours reported in patients with cirrhosis.132 133
Following IV administration, decreased total body clearance in geriatric individuals compared with that in young adults .342
Tight, light resistant containers at 15–25°C; protect from light and moisture.284
Tight, light resistant containers at <30°C; protect from light and moisture.126 342
Inhibits transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations.126 284 342
Peripheral arterial vasodilator; acts directly on vascular smooth muscle causing reduction in peripheral vascular resistance (afterload) and BP.126 284 342
Importance of swallowing extended-release tablets whole; do not chew, crush, or break.126 342
Importance of advising patients receiving extended-release tablets that tablet core may be excreted in stools without affecting drug efficacy.126
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.126 284 342
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.126 284 342
Importance of informing patients of other important precautionary information.126 284 342 (See Cautions.)
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
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules, liquid-filled | 10 mg* | Adalat | Bayer |
Procardia | Pfizer | |||
20 mg* | Adalat | Bayer | ||
Procardia | Pfizer | |||
Tablets, extended-release, film-coated | 30 mg* | Adalat CC | Bayer | |
Nifedical XL | Teva | |||
Nifedipine ER | Mylan, Teva, Watson | |||
Procardia XL | Pfizer | |||
60 mg* | Adalat CC | Bayer | ||
Nifedical XL | Teva | |||
Nifedipine ER | Mylan, Teva, Watson | |||
Procardia XL | Pfizer | |||
90 mg* | Adalat CC | Bayer | ||
Nifedipine ER | Mylan | |||
Procardia XL | Pfizer |
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Adalat CC 30MG 24-hr Tablets (SCHERING): 30/$54.99 or 90/$140.97
Adalat CC 60MG 24-hr Tablets (SCHERING): 30/$80.99 or 90/$242.97
Adalat CC 90MG 24-hr Tablets (SCHERING): 30/$98.62 or 90/$269.89
Afeditab CR 30MG 24-hr Tablets (WATSON LABS): 30/$46.52 or 90/$116.29
Afeditab CR 60MG 24-hr Tablets (WATSON LABS): 30/$63.86 or 90/$181.5
Nifediac CC 60MG 24-hr Tablets (TEVA PHARMACEUTICALS USA): 30/$49.99 or 90/$125.96
Nifediac CC 90MG 24-hr Tablets (TEVA PHARMACEUTICALS USA): 30/$60.99 or 90/$170.99
NIFEdipine 10MG Capsules (ACTAVIS ELIZABETH): 90/$72.69 or 180/$132.15
NIFEdipine 20MG Capsules (ACTAVIS ELIZABETH): 90/$149.99 or 270/$435.96
NIFEdipine CR Osmotic 90MG 24-hr Tablets (MYLAN): 30/$75.99 or 90/$185.97
Procardia 10MG Capsules (PFIZER U.S.): 90/$107.33 or 270/$305.74
Procardia XL 30MG 24-hr Tablets (PFIZER U.S.): 30/$75.99 or 90/$200.96
Procardia XL 60MG 24-hr Tablets (PFIZER U.S.): 30/$122.37 or 90/$341.74
Procardia XL 90MG 24-hr Tablets (PFIZER U.S.): 30/$138.91 or 90/$396.89
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 March 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Only references cited for selected revisions after 1984 are available electronically.
100. Kleinbloesem CH, van Brummelen P, Woittiez AJ et al. Influence of haemodialysis on the pharmacokinetics and haemodynamic effects of nifedipine during continuous intravenous infusion. Clin Pharmacokinet. 1986; 11:316-22. [IDIS 220845] [PubMed 3757391]
101. Hansten PD. Drug interactions. 5th ed. Philadelphia: Lea & Febiger; 1985; 279-85.
102. Pedersen KE, Dorph-Pedersen A, Hvidt S et al. Effect of nifedipine on digoxin kinetics in healthy subjects. Clin Pharmacol Ther. 1982; 32:562-5. [IDIS 160296] [PubMed 7127997]
103. Schwartz JB, Migliore PJ. Effect of nifedipine on serum digoxin concentration and renal digoxin clearance. Clin Pharmacol Ther. 1984; 36:19-24. [IDIS 187547] [PubMed 6734045]
104. Schwartz JB, Raizner A, Akers S. The effect of nifedipine on serum digoxin concentrations in patients. Am Heart J. 1984; 107:669-73. [IDIS 184991] [PubMed 6702561]
105. Garty M, Shamir E, Ilfeld D et al. Noninteraction of digoxin and nifedipine in cardiac patients. J Clin Pharmacol. 1986; 26:304-5. [IDIS 214557] [PubMed 3700685]
106. Belz GG, Doering W, Munkes R et al. Interaction between digoxin and calcium antagonists and antiarrhythmic drugs. Clin Pharmacol Ther. 1983; 33:410-7. [IDIS 169079] [PubMed 6831819]
107. Kirch W, Hutt HJ, Dylewicz P et al. Dose-dependence of the nifedipine-digoxin interaction. Clin Pharmacol Ther. 1986; 39:35-9. [IDIS 211183] [PubMed 3943268]
108. Pfizer Laboratories. Procardia (nifedipine) capsules prescribing information. In: Huff BB, ed. Physicians’ desk reference. 40th ed. Oradell, NJ: Medical Economics Company Inc; 1986:1423-4.
109. Houston MC. Treatment of hypertensive urgencies and emergencies with nifedipine. Am Heart J. 1986; 111:963-9. [IDIS 215245] [PubMed 3518379]
110. Haft JI, Litterer WE III. Chewing nifedipine to rapidly treat hypertension. Arch Intern Med. 1984; 144:1357-9.
111. Bertel O, Conen D, Radu EW et al. Nifedipine in hypertensive emergencies. BMJ. 1983; 286:19-21. [IDIS 163425] [PubMed 6401442]
112. Huysmans FTM, Sluiter HE, Thien TA et al. Acute treatment of hypertensive crisis with nifedipine. Br J Clin Pharmacol. 1983; 16:725-7. [IDIS 180054] [PubMed 6661359]
113. Lacche A, Basaglia P. Hypertensive emergencies: effects of therapy by nifedipine administered sublingually. Curr Ther Res. 1983; 34:879-87.
114. Pfizer Laboratories Division. Procardia (nifedipine) capsules prescribing information dated Feb 1993. In: Physicians’ desk reference. 48th ed. Montvale, NJ: Medical Economics Company Inc; 1994; 1795-6.
115. Mangini RJ, ed. Drug interaction facts. St. Louis: JB Lippincott Co; 1985(Oct):405a.
116. Kirch W, Ohnhaus EE, Hoensch H et al. Ranitidine increases bioavailability of nifedipine. Clin Pharmacol Ther. 1985; 37:204.
117. Adler AG, Leahy JJ, Cressman MD. Management of perioperative hypertension using sublingual nifedipine: experience in elderly patients undergoing eye surgery. Arch Intern Med. 1986; 146:1927-30. [IDIS 222084] [PubMed 3767537]
118. Houston MC. The comparative efficacy of clonidine hydrochloride and nifedipine in the treatment of hypertensive crises. Am Heart J. 1988; 115:152-9. [IDIS 237763] [PubMed 3276107]
119. Wachter RM. Symptomatic hypotension induced by nifedipine in the acute treatment of severe hypertension. Arch Intern Med. 1987; 147:556-8. [IDIS 227163] [PubMed 3827433]
120. Frishman WH, Charlap S. Nifedipine in the treatment of systemic hypertension. Arch Intern Med. 1984; 144:2335-6. [IDIS 193036] [PubMed 6508440]
121. Ferlinz J. Nifedipine in myocardial ischemia, systemic hypertension, and other cardiovascular disorders. Ann Intern Med. 1986; 105:714-29. [IDIS 222904] [PubMed 3532894]
122. Jennings AA, Jee LD, Smith JA et al. Acute e
Haidesin may be available in the countries listed below.
Benzalkonium chloride (a derivative of Benzalkonium) is reported as an ingredient of Haidesin in the following countries:
International Drug Name Search
Increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS). Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore, use in EBV seropositive patients only. Do not use Nulojix in transplant recipients who are EBV seronegative or with unknown EBV serostatus [see Contraindications (4) and Warnings and Precautions (5.1)].
Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe Nulojix. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see Warnings and Precautions (5.2)].
Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression [see Warnings and Precautions (5.1, 5.3, 5.4, 5.5)].
Use in liver transplant patients is not recommended due to an increased risk of graft loss and death [see Warnings and Precautions (5.6)].
Nulojix® (belatacept) is indicated for prophylaxis of organ rejection in adult patients receiving a kidney transplant. Nulojix is to be used in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids.
Use Nulojix only in patients who are EBV seropositive [see Contraindications (4) and Warnings and Precautions (5.1)].
Use of Nulojix for the prophylaxis of organ rejection in transplanted organs other than kidney has not been established [see Warnings and Precautions (5.6)].
Due to an increased risk of post-transplant lymphoproliferative disorder (PTLD) predominantly involving the central nervous system (CNS), progressive multifocal leukoencephalopathy (PML), and serious CNS infections, administration of higher than the recommended doses or more frequent dosing of Nulojix is not recommended [see Warnings and Precautions (5.1, 5.4, 5.5) and Adverse Reactions (6.1)].
Nulojix is for intravenous infusion only. Patients do not require premedication prior to administration of Nulojix.
Dosing instructions are provided in Table 1.
| Dosing for Initial Phase | Dose | ||||
|---|---|---|---|---|---|
| * [See Clinical Studies (14.1).] | |||||
| † The dose prescribed for the patient must be evenly divisible by 12.5 mg (see instructions above; e.g., evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100) | |||||
| Day 1 (day of transplantation, prior to implantation) and Day 5 (approximately 96 hours after Day 1 dose) | 10 mg per kg | ||||
| End of Week 2 and Week 4 after transplantation | 10 mg per kg | ||||
| End of Week 8 and Week 12 after transplantation | 10 mg per kg | ||||
| Dosing for Maintenance Phase | Dose | ||||
| End of Week 16 after transplantation and every 4 weeks (plus or minus 3 days) thereafter | 5 mg per kg | ||||
Nulojix is for intravenous infusion only.
Caution: Nulojix must be reconstituted/prepared using only the silicone-free disposable syringe provided with each vial.
If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. For information on obtaining additional silicone-free disposable syringes, contact Bristol-Myers Squibb at 1-888-Nulojix.
Note: If the Nulojix powder is accidentally reconstituted using a different syringe than the one provided, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes.
Volume of 25 mg/mL Nulojix solution (in mL) = Prescribed Dose (in mg) ÷ 25 mg/mL
The final belatacept concentration in the infusion container should range from 2 mg/mL to 10 mg/mL. Typically, an infusion volume of 100 mL will be appropriate for most patients and doses, but total infusion volumes ranging from 50 mL to 250 mL may be used. Any unused solution remaining in the vials must be discarded.
Lyophilized powder for injection: 250 mg per vial.
Nulojix is contraindicated in transplant recipients who are Epstein-Barr virus (EBV) seronegative or with unknown EBV serostatus due to the risk of post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS) [see Boxed Warning and Warnings and Precautions (5.1)].
Nulojix-treated patients have an increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the CNS, compared to patients on a cyclosporine-based regimen [see Adverse Reactions (6.1) and Table 2]. As the total burden of immunosuppression is a risk factor for PTLD, higher than the recommended doses or more frequent dosing of Nulojix and higher than recommended doses of concomitant immunosuppressive agents are not recommended [see Dosage and Administration (2.1) and Warnings and Precautions (5.6)]. Physicians should consider PTLD in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms.
The risk of PTLD was higher in EBV seronegative patients compared to EBV seropositive patients. EBV seropositive patients are defined as having evidence of acquired immunity shown by the presence of IgG antibodies to viral capsid antigen (VCA) and EBV nuclear antigen (EBNA).
Epstein-Barr virus serology should be ascertained before starting administration of Nulojix, and only patients who are EBV seropositive should receive Nulojix. Transplant recipients who are EBV seronegative, or with unknown serostatus, should not receive Nulojix [see Boxed Warning and Contraindications (4)].
Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T-cell-depleting therapy. T-cell-depleting therapies to treat acute rejection should be used cautiously. CMV prophylaxis is recommended for at least 3 months after transplantation [see Warnings and Precautions (5.5)].
Patients who are EBV seropositive and CMV seronegative may be at increased risk for PTLD compared to patients who are EBV seropositive and CMV seropositive [see Adverse Reactions (6.1)]. Since CMV seronegative patients are at increased risk for CMV disease (a known risk factor for PTLD), the clinical significance of CMV serology for PTLD remains to be determined; however, these findings should be considered when prescribing Nulojix.
Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe Nulojix. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient [see Boxed Warning].
Patients receiving immunosuppressants, including Nulojix, are at increased risk of developing malignancies, in addition to PTLD, including the skin [see Boxed Warning and Warnings and Precautions (5.1)]. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Progressive multifocal leukoencephalopathy (PML) is an often rapidly progressive and fatal opportunistic infection of the CNS that is caused by the JC virus, a human polyoma virus. In clinical trials with Nulojix, two cases of PML were reported in patients receiving Nulojix at higher cumulative doses and more frequently than the recommended regimen, along with mycophenolate mofetil (MMF) and corticosteroids; one case occurred in a kidney transplant recipient and the second case occurred in a liver transplant recipient [see Warnings and Precautions (5.6)]. As PML has been associated with high levels of overall immunosuppression, the recommended doses and frequency of Nulojix and concomitant immunosuppressives, including MMF, should not be exceeded.
Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive, or behavioral signs or symptoms. PML is usually diagnosed by brain imaging, cerebrospinal fluid (CSF) testing for JC viral DNA by polymerase chain reaction (PCR), and/or brain biopsy. Consultation with a specialist (e.g., neurologist and/or infectious disease) should be considered for any suspected or confirmed cases of PML.
If PML is diagnosed, consideration should be given to reduction or withdrawal of immunosuppression taking into account the risk to the allograft.
Patients receiving immunosuppressants, including Nulojix, are at increased risk of developing bacterial, viral (cytomegalovirus [CMV] and herpes), fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes [see Boxed Warning and Adverse Reactions (6.1)].
Prophylaxis for cytomegalovirus is recommended for at least 3 months after transplantation. Prophylaxis for Pneumocystis jiroveci is recommended after transplantation.
Tuberculosis was more frequently observed in patients receiving Nulojix than cyclosporine in clinical trials [see Adverse Reactions (6.1)]. Patients should be evaluated for tuberculosis and tested for latent infection prior to initiating Nulojix. Treatment of latent tuberculosis infection should be initiated prior to Nulojix use.
In addition to cases of JC virus-associated PML [see Warnings and Precautions (5.4)], cases of polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, have been reported. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss [see Adverse Reactions (6.1)]. Patient monitoring may help detect patients at risk for PVAN. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.
Use of Nulojix in liver transplant patients is not recommended [see Boxed Warning]. In a clinical trial of liver transplant patients, use of Nulojix regimens with more frequent administration of belatacept than any of those studied in kidney transplant, along with mycophenolate mofetil (MMF) and corticosteroids, was associated with a higher rate of graft loss and death compared to the tacrolimus control arms. In addition, two cases of PTLD involving the liver allograft (one fatal) and one fatal case of PML were observed among the 147 patients randomized to Nulojix. The two cases of PTLD were reported among the 140 EBV seropositive patients (1.4%). The fatal case of PML was reported in a patient receiving higher than recommended doses of Nulojix and MMF [see Warnings and Precautions (5.4)].
The use of live vaccines should be avoided during treatment with Nulojix, including but not limited to the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
The most serious adverse reactions reported with Nulojix are:
The data described below primarily derive from two randomized, active-controlled three-year trials of Nulojix in de novo kidney transplant patients. In Study 1 and Study 2, Nulojix was studied at the recommended dose and frequency [see Dosage and Administration (2.1)] in a total of 401 patients compared to a cyclosporine control regimen in a total of 405 patients. These two trials also included a total of 403 patients treated with a Nulojix regimen of higher cumulative dose and more frequent dosing than recommended [see Clinical Studies (14.1)]. All patients also received basiliximab induction, mycophenolate mofetil, and corticosteroids. Patients were treated and followed for 3 years.
CNS PTLD, PML, and other CNS infections were more frequently observed in association with a Nulojix regimen of higher cumulative dose and more frequent dosing compared to the recommended regimen; therefore, administration of higher than the recommended doses and/or more frequent dosing of Nulojix is not recommended [see Dosage and Administration (2.1)].
The average age of patients in Studies 1 and 2 in the Nulojix recommended dose and cyclosporine control regimens was 49 years, ranging from 18 to 79 years. Approximately 70% of patients were male; 67% were white, 11% were black, and 22% other races. About 25% of patients were from the United States and 75% from other countries.
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
The most commonly reported adverse reactions occurring in ≥20% of patients treated with the recommended dose and frequency of Nulojix were anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia.
The proportion of patients who discontinued treatment due to adverse reactions was 13% for the recommended Nulojix regimen and 19% for the cyclosporine control arm through three years of treatment. The most common adverse reactions leading to discontinuation in Nulojix-treated patients were cytomegalovirus infection (1.5%) and complications of transplanted kidney (1.5%).
Information on selected significant adverse reactions observed during clinical trials is summarized below.
Reported cases of post-transplant lymphoproliferative disorder (PTLD) up to 36 months post transplant were obtained for Nulojix by pooling both dosage regimens of Nulojix in Studies 1 and 2 (804 patients) with data from a third study in kidney transplantation (Study 3, 145 patients) which evaluated two Nulojix dosage regimens similar, but slightly different, from those of Studies 1 and 2 (see Table 2). The total number of Nulojix patients from these three studies (949) was compared to the pooled cyclosporine control groups from all three studies (476 patients).
Among 401 patients in Studies 1 and 2 treated with the recommended regimen of Nulojix and the 71 patients in Study 3 treated with a very similar (but non-identical) Nulojix regimen, there were 5 cases of PTLD: 3 in EBV seropositive patients and 2 in EBV seronegative patients. Two of the 5 cases presented with CNS involvement.
Among the 477 patients in Studies 1, 2, and 3 treated with the Nulojix regimen of higher cumulative dose and more frequent dosing than recommended, there were 8 cases of PTLD: 2 in EBV seropositive patients and 6 in EBV seronegative or serostatus unknown patients. Six of the 8 cases presented with CNS involvement. Therefore, administration of higher than the recommended doses or more frequent dosing of Nulojix is not recommended. [See Dosage and Administration (2.1) and Warnings and Precautions (5.1).]
One of the 476 patients treated with cyclosporine developed PTLD, without CNS involvement.
All cases of PTLD reported up to 36 months post transplant in Nulojix- or cyclosporine-treated patients presented within 18 months of transplantation.
Overall, the rate of PTLD in 949 patients treated with any of the Nulojix regimens was 9-fold higher in those who were EBV seronegative or EBV serostatus unknown (8/139) compared to those who were EBV seropositive (5/810 patients). Therefore Nulojix is recommended for use only in patients who are EBV seropositive [see Boxed Warning and Contraindications (4)].
| Nulojix Non-Recommended Regimen* (N=477) | Nulojix Recommended Regimen† (N=472) | Cyclosporine (N=476) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Trial | EBV Positive (n=406) | EBV Negative (n=43) | EBV Unknown (n=28) | EBV Positive (n=404) | EBV Negative (n=48) | EBV Unknown (n=20) | EBV Positive (n=399) | EBV Negative (n=57) | EBV Unknown (n=20) |
| * Regimen with higher cumulative dose and more frequent dosing than the recommended Nulojix regimen. | |||||||||
| † In Studies 1 and 2 the Nulojix regimen is identical to the recommended regimen, but is slightly different in Study 3. | |||||||||
| Study 1 | |||||||||
| CNS PTLD | 1 | 1 | |||||||
| Non-CNS PTLD | 1 | 2 | 1 | ||||||
| Study 2 | |||||||||
| CNS PTLD | 1 | 1 | 1 | 1 | |||||
| Non-CNS PTLD | 1 | ||||||||
| Study 3 | |||||||||
| CNS PTLD | 2 | ||||||||
| Non-CNS PTLD | 1 | ||||||||
| Total (%) | 2 (0.5) | 5 (11.6) | 1 (3.6) | 3 (0.7) | 2 (4.1) | 0 | 0 | 1 (1.8) | 0 |
Among the 806 EBV seropositive patients with known CMV serostatus treated with either Nulojix regimen in Studies 1, 2, and 3, two percent (2%; 4/210) of CMV seronegative patients developed PTLD compared to 0.2% (1/596) of CMV seropositive patients. Among the 404 EBV seropositive recipients treated with the recommended dosage regimen of Nulojix, three PTLD cases were detected among 99 CMV seronegative patients (3%) and there was no case detected among 303 CMV seropositive patients. The clinical significance of CMV serology as a risk factor for PTLD remains to be determined; however, these findings should be considered when prescribing Nulojix [see Warnings and Precautions (5.1)].
Malignancies, excluding non-melanoma skin cancer and PTLD, were reported in Study 1 and Study 2 in 3.5% (14/401) of patients treated with the recommended Nulojix regimen and 3.7% (15/405) of patients treated with the cyclosporine control regimen. Non-melanoma skin cancer was reported in 1.5% (6/401) of patients treated with the recommended Nulojix regimen and in 3.7% (15/405) of patients treated with cyclosporine [see Warnings and Precautions (5.3)].
Two fatal cases of progressive multifocal leukoencephalopathy (PML) have been reported among 1096 patients treated with a Nulojix-containing regimen: one patient in clinical trials of kidney transplant (Studies 1, 2, and 3 described above) and one patient in a trial of liver transplant (trial of 250 patients). No cases of PML were reported in patients treated with the recommended Nulojix regimen or the control regimen in these trials.
The kidney transplant recipient was treated with the Nulojix regimen of higher cumulative dose and more frequent dosing than recommended, mycophenolate mofetil (MMF), and corticosteroids for 2 years. The liver transplant recipient was treated with 6 months of a Nulojix dosage regimen that was more intensive than that studied in kidney transplant recipients, MMF at doses higher than the recommended dose, and corticosteroids [see Warnings and Precautions (5.4)].
Adverse reactions of infectious etiology were reported based on clinical assessment by physicians. The causative organisms for these reactions are identified when provided by the physician. The overall number of infections, serious infections, and select infections with identified etiology reported in patients treated with the Nulojix recommended regimen or the cyclosporine control in Studies 1 and 2 are shown in Table 3. Fungal infections were reported in 18% of patients receiving Nulojix compared to 22% receiving cyclosporine, primarily due to skin and mucocutaneous fungal infections. Tuberculosis and herpes infections were reported more frequently in patients receiving Nulojix than cyclosporine. Of the patients who developed tuberculosis through 3 years, all but one Nulojix patient lived in countries with a high prevalence of tuberculosis [see Warnings and Precautions (5.5)].
| Up to Year 1 | Up to Year 3† | |||
|---|---|---|---|---|
| Nulojix Recommended Regimen N=401 n (%) | Cyclosporine N=405 n (%) | Nulojix Recommended Regimen N=401 n (%) | Cyclosporine N=405 n (%) | |
| * Studies 1 and 2 were not designed to support comparative claims for Nulojix for the adverse reactions reported in this table. | ||||
| † Median exposure in days for pooled studies: 1203 for Nulojix recommended regimen and 1163 for cyclosporine in Studies 1 and 2. | ||||
| ‡ All infections include bacterial, viral, fungal, and other organisms. For infectious adverse reactions, the causative organism is reported if specified by the physician in the clinical trials. | ||||
| § A medically important event that may be life-threatening or result in death or hospitalization or prolongation of existing hospitalization. Infections not meeting these criteria are considered non-serious. | ||||
| ¶ BK virus-associated nephropathy was reported in 6 Nulojix patients (4 of which resulted in graft loss) and 6 cyclosporine patients (none of which resulted in graft loss) by Year 3. | ||||
| # Most herpes infections were non-serious and 1 led to treatment discontinuation. | ||||
| All infections‡ | 287 (72) | 299 (74) | 329 (82) | 327 (81) |
| Serious infections§ | 98 (24) | 113 (28) | 144 (36) | 157 (39) |
| CMV | 44 (11) | 52 (13) | 53 (13) | 56 (14) |
| Polyoma virus¶ | 10 (3) | 23 (6) | 17 (4) | 27 (7) |
| Herpes# | 27 (7) | 26 (6) | 55 (14) | 46 (11) |
| Tuberculosis | 2 (1) | 1 (<1) | 6 (2) | 1 (<1) |
Following three years of treatment in Studies 1 and 2, cryptococcal meningitis was reported in one patient out of 401 patients treated with the Nulojix recommended regimen (0.2%) and one patient out of the 405 treated with the cyclosporine control (0.2%).
Six patients out of the 403 who were treated with the Nulojix regimen of higher cumulative dose and more frequent dosing than recommended in Studies 1 and 2 (1.5%) were reported to have developed CNS infections, including 2 cases of cryptococcal meningitis, one case of Chagas encephalitis with cryptococcal meningitis, one case of cerebral aspergillosis, one case of West Nile encephalitis, and one case of PML (discussed above).
There were no reports of anaphylaxis or drug hypersensitivity in patients treated with Nulojix in Studies 1 and 2 through three years.
Infusion-related reactions within one hour of infusion were reported in 5% of patients treated with the recommended dose of Nulojix, similar to the placebo rate. No serious events were reported through Year 3. The most frequent reactions were hypotension and hypertension.
At Month 1 after transplantation in Studies 1 and 2, the frequency of 2+ proteinuria on urine dipstick in patients treated with the Nulojix recommended regimen was 33% (130/390) and 28% (107/384) in patients treated with the cyclosporine control regimen. The frequency of 2+ proteinuria was similar between the two treatment groups between one and three years after transplantation (<10% in both studies). There were no differences in the occurrence of 3+ proteinuria (<4% in both studies) at any time point, and no patients experienced 4+ proteinuria. The clinical significance of this increase in early proteinuria is unknown.
Antibodies directed against the belatacept molecule were assessed in 398 patients treated with the Nulojix recommended regimen in Studies 1 and 2 (212 of these patients were treated for at least 2 years). Of the 372 patients with immunogenicity assessment at baseline (prior to receiving belatacept treatment), 29 patients tested positive for anti-belatacept antibodies; 13 of these patients had antibodies to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Anti-belatacept antibody titers did not increase during treatment in these 29 patients.
Eight (2%) patients developed antibodies during treatment with the Nulojix recommended regimen. In the patients who developed antibodies during treatment, the median titer (by dilution method) was 8, with a range of 5 to 80. Of 56 patients who tested negative for antibodies during treatment and reassessed approximately 7 half-lives after discontinuation of Nulojix, 1 tested antibody positive. Anti-belatacept antibody development was not associated with altered clearance of belatacept.
Samples from 6 patients with confirmed binding activity to the modified cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) region of the belatacept molecule were assessed by an in vitro bioassay for the presence of neutralizing antibodies. Three of these 6 patients tested positive for neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.
The clinical impact of anti-belatacept antibodies (including neutralizing anti-belatacept antibodies) could not be determined in the studies.
The data reflect the percentage of patients whose test results were positive for antibodies to belatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belatacept with the incidence of antibodies to other products may be misleading.
The incidence of new-onset diabetes after transplantation (NODAT) was defined in Studies 1 and 2 as use of an antidiabetic agent for ≥30 days or ≥2 fasting plasma glucose values ≥126 mg/dL (7.0 mmol/L) post-transplantation. Of the patients treated with the Nulojix recommended regimen, 5% (14/304) developed NODAT by the end of one year compared to 10% (27/280) of patients on the cyclosporine control regimen. However, by the end of the third year, the cumulative incidence of NODAT was 8% (24/304) in patients treated with the Nulojix recommended regimen and 10% (29/280) in patients treated with the cyclosporine regimen.
Blood pressure and use of antihypertensive medications were reported in Studies 1 and 2. By Year 3, one or more antihypertensive medications were used in 85% of Nulojix-treated patients and 92% of cyclosporine-treated patients. At one year after transplantation, systolic blood pressures were 8 mmHg lower and diastolic blood pressures were 3 mmHg lower in patients treated with the Nulojix recommended regimen compared to the cyclosporine control regimen. At three years after transplantation, systolic blood pressures were 6 mmHg lower and diastolic blood pressures were 3 mmHg lower in Nulojix-treated patients compared to cyclosporine-treated patients. Hypertension was reported as an adverse reaction in 32% of Nulojix-treated patients and 37% of cyclosporine-treated patients (see Table 4).
Mean values of total cholesterol, HDL, LDL, and triglycerides were reported in Studies 1 and 2. At one year after transplantation these values were 183 mg/dL, 50 mg/dL, 102 mg/dL, and 151 mg/dL, respectively, in 401 patients treated with the Nulojix recommended regimen and 196 mg/dL, 48 mg/dL, 108 mg/dL, and 195 mg/dL, respectively, in 405 patients treated with the cyclosporine control regimen. At three years after transplantation, the total cholesterol, HDL, LDL, and triglycerides were 176 mg/dL, 49 mg/dL, 100 mg/dL, and 141 mg/dL, respectively, in Nulojix-treated patients compared to 193 mg/dL, 48 mg/dL, 106 mg/dL, and 180 mg/dL in cyclosporine-treated patients.
The clinical significance of the lower mean triglyceride values in Nulojix-treated patients at one and three years is unknown.
Adverse reactions that occurred at a frequency of ≥10% in patients treated with the Nulojix recommended regimen or cyclosporine control regimen in Studies 1 and 2 through three years are summarized by preferred term in decreasing order of frequency within Table 4.
| Adverse Reaction | Nulojix Recommended Regimen N=401 % | Cyclosporine N=405 % | ||
|---|---|---|---|---|
| * All randomized and transplanted patients in Studies 1 and 2. | ||||
| † Studies 1 and 2 were not designed to support comparative claims for Nulojix for the adverse reactions reported in this table. | ||||
| Infections and Infestations | ||||
| Urinary tract infection | 37 | 36 | ||
| Upper respiratory infection | 15 | 16 | ||
| Nasopharyngitis | 13 | 16 | ||
| Cytomegalovirus infection | 12 | 12 | ||
| Influenza | 11 | 8 | ||
| Bronchitis | 10 | 7 | ||
| Gastrointestinal Disorders | ||||
| Diarrhea | 39 | 36 | ||
| Constipation | 33 | 35 | ||
| Nausea | 24 | 27 | ||
| Vomiting | 22 | 20 | ||
| Abdominal pain | 19 | 16 | ||
| Abdominal pain upper | 9 | 10 | ||
| Metabolism and Nutrition Disorders | ||||
| Hyperkalemia | 20 | 20 | ||
| Hypokalemia | 21 | 14 | ||
| Hypophosphatemia | 19 | 13 | ||
| Dyslipidemia | 19 | |||
