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    Dihydropyridine Calcium Channel Blockers

    DEA CLASS

    Rx

    DESCRIPTION

    Oral calcium-channel blocker; prototype dihydropyridine with more prominent effects on vasodilation and coronary flow than diltiazem and verapamil; lacks effects on AV conduction; primarily used for angina, Prinzmetal's angina, and HTN.

    COMMON BRAND NAMES

    Adalat, Adalat CC, Afeditab CR, Nifediac CC, Nifedical XL, Procardia, Procardia XL

    HOW SUPPLIED

    Adalat CC/Afeditab CR/Nifediac CC/Nifedical XL/Nifedipine/Procardia XL Oral Tab ER: 30mg, 60mg, 90mg
    Adalat/Nifedipine/Procardia Oral Cap: 10mg, 20mg

    DOSAGE & INDICATIONS

    For the treatment of ischemic heart disease including variant angina (Prinzmetal's angina) and chronic stable angina pectoris.
    Oral dosage - immediate-release capsules
    Adults

    Initially, 10 mg PO 3 times daily. Titrate upwards as necessary. Maximum dosage is 180 mg/day PO; however, doses greater than 120 mg/day are rarely needed. Single dose maximum is 30 mg, unless using extended-release tablets.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Nifedipine plasma concentrations and half-life are significantly increased in geriatric patients. Adjust dosage based on clinical response.

    Oral dosage - extended-release tablets (e.g. Procardia XL and generic equivalents)
    Adults

    Initially, 30 to 60 mg PO once daily. Titrate upwards as necessary. Maximum dosage is 90 mg/day PO.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Nifedipine plasma concentrations and half-life are significantly increased in geriatric patients. Adjust dosage based on clinical response.

    For the treatment of hypertension.
    For acute hypertensive episodes including hypertensive urgency and hypertensive emergency in pediatric patients†.
    NOTE: Per the FDA and manufacturers, immediate-release nifedipine dosage forms should not be used to treat hypertension and should only be used to treat patients with chronic stable angina or vasospastic angina. The immediate-release nifedipine formulation has been associated with serious side effects (see Precautions and Adverse Reactions) when used to treat adult patients with hypertension, hypertensive urgency, hypertensive emergency, or coexisting myocardial infarction. Although the use of immediate-release nifedipine for the treatment of acute hypertensive episodes is still relatively common practice in pediatric patients, considerable controversy exists and caution should be used.
    Oral dosage - immediate-release capsules†
    Infants†, Children†, and Adolescents†

    A wide dosage range of immediate-release nifedipine has been reported in pediatric patients, however the most commonly reported doses range from 0.2 to 0.5 mg/kg/dose up to 10 mg total dose PO. Doses may be repeated every 4 to 6 hours. Some patients may experience a precipitous and unexpected drop in blood pressure, therefore some authors recommend initial doses of less than 0.2 mg/kg and avoiding the use of nifedipine immediate-release in patients with CNS injury. One retrospective study of 182 pediatric patients aged 0.2 to 17.9 years described the use of immediate-release nifedipine for severe hypertension. The mean dose of nifedipine used was 0.22 mg/kg PO (range 0.04 to 0.67 mg/kg), and the authors reported resolution of hypertension in 85.5% of the 477 episodes. The mean reductions in systolic blood pressures (SBP) and diastolic blood pressures (DBP) respectively were 16.9% and 24.7%, and 2 patients experienced a drop in blood pressure of greater than 40%. Another retrospective study examined 117 patients aged 0.1 to 18.9 years who received immediate-release nifedipine for the treatment of acute hypertensive episodes with SBP and DBP greater than 95th percentile for sex, age, and height. The mean nifedipine dose used was 0.23 mg/kg (range 0.04 to 0.69 mg/kg) PO. Of the 520 doses administered, 24% and 43% resulted in a greater than 25% reduction in SBP and DBP respectively, and the degree of blood pressure reduction was weakly correlated to the mg/kg dose. No clinically significant adverse events were noted.

    Oral dosage - extended-release tablets
    Adults

    Initially, 30 to 60 mg PO once daily. Titrate upwards as necessary. Maximum dosage recommended by the product labeling is 90 mg/day for most formulations of extended-release products; however, the maximum dosing for Procardia XL is 120 mg/day.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Nifedipine plasma concentrations and half-life are significantly increased in geriatric patients. Adjust dosage based on clinical response.

    Children† and Adolescents†

    Initial doses ranging from 0.25 to 0.5 mg/kg/day PO have been suggested. Titration as needed up to a maximum of 3 mg/kg/day PO, not to exceed 120 mg/day, has been recommended by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents ; however, some experts recommend that doses up to 180 mg/day may be necessary in some clinical situations. Dosage may be given once daily or in 2 divided doses administered every 12 hours. NOTE: Extended-release tablets must be swallowed whole and are too large for young children.

    For migraine prophylaxis†.
    Oral dosage
    Adults

    Doses of 30—180 mg/day PO have been recommended. Doses above 120 mg/day are rarely required.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Nifedipine plasma concentrations and half-life are significantly increased in geriatric patients. Adjust dosage based on clinical response.

    For the treatment of proteinuria† associated with diabetic nephropathy†.
    Oral dosage
    Adults

    Conflicting data exist regarding the use of nifedipine for proteinuria associated with diabetic nephropathy. A significant increase in urinary albumin excretion was reported in 7 normotensive patients with diabetic nephropathy who were treated with slow-release nifedipine 20 mg PO twice daily and followed for 6 weeks. A significant increase in urinary albumin excretion was also reported in a crossover study of 14 non-insulin dependent diabetic patients during a 20-week trial. The mean study dose was 45 +/- 8 mg of long-acting nifedipine once daily. Conversely, in another study, 27 diabetics with persistent microalbuminuria received nifedipine 20 to 80 mg PO once daily for 12 months. These data demonstrated a decrease in urinary albumin excretion (UAE) during therapy, however, UAE increased to levels greater than baseline once therapy was discontinued.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Nifedipine plasma concentrations and half-life are significantly increased in geriatric patients. Adjust dosage based on clinical response.

    For the treatment of persistent singultus (hiccups)†.
    Oral dosage
    Adults

    Doses of 10 to 20 mg PO 3 times daily have been used.

    Geriatric

    See adult dosage. In general, initiate dosage at the lower end of the adult dosage range. Nifedipine plasma concentrations and half-life are significantly increased in geriatric patients. Adjust dosage based on clinical response.

    For the inhibition of uterine contractions in premature labor†.
    NOTE: Clinical practice guidelines recommend the use of a first line tocolytic (i.e., beta agonist, calcium channel blocker, or NSAID) for short-term use (up to 48 hours) to allow for administration of antenatal corticosteroids to enhance fetal lung maturation, magnesium sulfate for fetal neuroprotection, or transport to a tertiary facility, if indicated. There is no evidence that tocolytic therapy alone has any favorable effect on neonatal outcomes. Maintenance therapy with tocolytics is ineffective for preventing preterm birth and improving neonatal outcomes and is not recommended.
    Oral dosage - immediate-release (Procardia)
    Pregnant females

    Various regimens have been used. The recommended dose by the American College of Obstetrics and Gynecology (ACOG) is a 30-mg loading dose, followed by 10 to 20 mg every 4 to 6 hours. NOTE: A route of administration is not provided, although typically PO and/or SL is used for the loading dose and PO is used for subsequent dosing. Typical regimens for the loading dose include 10 mg SL with 20 mg PO, 30 mg PO, or 10 to 20 mg SL or PO every 15 to 20 minutes until contractions stop, up to a maximum of 30 to 40 mg over 1 hour. Although not definitive, typical duration of tocolysis for acute inhibition of premature labor is 24 to 72 hours. When compared to ritodrine or magnesium sulfate, nifedipine has generally demonstrated similar efficacy with similar or fewer maternal side effects. Although maintenance use of tocolytics after acute suppression of contractions has not been shown to prolong pregnancy, doses of 10 to 20 mg PO every 4 to 6 hours have been used. Additionally, some studies have used maintenance dosing with slow-release nifedipine (doses of 60 to 160 mg/day PO). Magnesium sulfate therapy should not be given concurrently because of additive effects on maternal cardiac function.

    For the treatment of achalasia†.
    Oral or Sublingual† dosage
    Adults

    10 to 30 mg PO or SL, 30 to 45 minutes before meals. Nifedipine inhibits lower esophageal (LES) muscle contraction by blocking cellular calcium uptake and lowers the LES resting pressure by 30% to 60%; side effects (e.g., hypotension, headache, dizziness) and tolerance may limit its utility. Reserve oral therapy for patients who refuse or are not candidates for more definitive therapies (pneumatic dilation or surgical myotomy) or who fail to respond to botulinum toxin injections.

    For the treatment of high altitude pulmonary edema associated with altitude sickness†.
    Oral dosage (extended-release tablets)
    Children and Adolescents

    0.5 mg/kg/dose PO every 8 hours (Max: 40 mg/dose) is recommended in an international consensus statement. Of note, 20 mg/dose every 8 hours is the maximum adult dosage recommended by clinical practice guidelines. The extended-release formulation is preferred over immediate-release. Descent and oxygen are the preferred initial treatments; nifedipine is considered a second line treatment and is recommended only when the response to first line treatments is not satisfactory.

    Adults

    30 mg PO every 12 hours or 20 mg PO every 8 hours, as adjunct to descent and/or oxygen, is recommended by clinical practice guidelines. Nifedipine should not be used as monotherapy unless descent is not possible and access to oxygen or portable hyperbaric therapy is not feasible.

    Oral dosage (immediate-release capsules)
    Children and Adolescents

    0.5 mg/kg/dose PO every 8 hours (Max: 20 mg/dose) is recommended in an international consensus statement. Of note, 10 mg/dose is the usual maximum dosage for other indications (e.g., hypertensive crisis). The extended-release formulation is preferred over immediate-release. Descent and oxygen are the preferred initial treatments; nifedipine is considered a second line treatment and is recommended only when the response to first line treatments is not satisfactory.

    For altitude sickness prophylaxis, specifically prevention of high altitude pulmonary edema.
    Oral dosage
    Adults

    30 mg PO every 12 hours or 20 mg PO every 8 hours is recommended in clinical practice guidelines. Slow ascent is the primary recommended method for prevention of high-altitude pulmonary edema (HAPE). Pharmacologic prophylaxis should only be considered for individuals with a prior history of HAPE, and nifedipine is preferred. Start prophylaxis the day prior to the ascent. Continue prophylaxis for 5 days after reaching target altitude or until descent is initiated.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    90 mg/day PO for Procardia XL or 180 mg/day PO for immediate-release capsules for angina; 90 mg/day PO for most extended-release tabs and 120 mg/day PO for Procardia XL for hypertension.

    Elderly

    90 mg/day PO for Procardia XL or 180 mg/day PO for immediate-release capsules for angina; 90 mg/day PO for most extended-release tabs and 120 mg/day PO for Procardia XL for hypertension.

    Adolescents

    Safety and efficacy have not been established; however, up to 3 mg/kg/day PO (not to exceed 180 mg/day) for extended-release tablets has been used off-label for hypertension; 0.5 mg/kg/dose (not to exceed 10 mg/dose) has been used off-label for hypertensive urgency/emergency.

    Children

    Safety and efficacy have not been established; however, up to 3 mg/kg/day PO (not to exceed 180 mg/day) for extended-release tablets has been used off-label for hypertension; 0.5 mg/kg/dose (not to exceed 10 mg/dose) has been used off-label for hypertensive urgency/emergency.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage reduction and close monitoring of blood pressure is advised in patients with hepatic impairment. Although no specific guidelines are available, the half-life and AUC of nifedipine is markedly increased in cirrhotic patients.

    Renal Impairment

    No dosage adjustment is needed.
     
    Intermittent hemodialysis
    Nifedipine is minimally removed by hemodialysis or hemoperfusion. Therefore, no supplemental dosage is needed following hemodialysis.

    ADMINISTRATION

    Oral Administration

    If gastric irritation becomes problematic, administer oral doses with meals. According to the manufacturer, Adalat CC should be administered on an empty stomach.
    Avoid grapefruit juice before or after drug administration to avoid potential increases in nifedipine bioavailability.

    Oral Solid Formulations

    Nifedipine immediate-release capsules and sustained-release tablets should be swallowed whole. Do not crush, break, or chew sustained-release tablets. Advise patient that empty tablet shells in the stool are not significant.
    Two 30 mg Adalat CC tablets may be interchanged with a 60 mg Adalat CC tablet. However, three 30 mg tablets will result in a substantially higher Cmax than a single 90 mg Adalat CC tablet. Therefore, three 30 mg tablets should not be considered interchangeable with a 90 mg tablet.

    Other Administration Route(s)

    Sublingual Administration†
    Not recommended. There is no difference in relative bioavailability when immediate-release capsules are administered whole, bitten and swallowed, or bitten and held sublingually. Sublingual administration offers no advantage over oral administration of the immediate-release capsules.

    STORAGE

    Adalat:
    - Avoid excessive humidity
    - Protect from freezing
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Adalat CC:
    - Avoid excessive humidity
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Afeditab CR:
    - Avoid excessive humidity
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Nifediac CC:
    - Avoid excessive humidity
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Nifedical XL:
    - Avoid excessive humidity
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Procardia:
    - Avoid excessive humidity
    - Protect from freezing
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Procardia XL:
    - Avoid excessive humidity
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Nifedipine decreases peripheral resistance and can worsen hypotension. Nifedipine should not be used in patients with systolic blood pressures of less than 90 mm Hg (i.e., severe hypotension). Nifedipine should be used with caution in patients with mild to moderate hypotension. Blood pressure should be monitored carefully in all patients receiving nifedipine.

    Dihydropyridine hypersensitivity

    Nifedipine is a dihydropyridine calcium-channel blocker and is contraindicated in patients with known serious dihydropyridine hypersensitivity.

    Pregnancy

    Nifedipine is classified as FDA pregnancy category C. According to the manufacturer, the drug should be used only when its benefits clearly outweigh the risks to the fetus. The manufacturer also notes a report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro.

    Breast-feeding

    Because nifedipine is excreted in human milk, the manufacturer does not recommend breast-feeding during nifedipine therapy. Based off of data from a single mother: infant pair, it has been estimated that the amount of drug that would appear in the breast-milk is < 5% of the maternal therapeutic dose. However, neonatal myocardium is very sensitive to changes in calcium status, and the therapeutic dose for a neonate is unknown. The authors further concluded that delaying breast-feeding or expressing milk for 3—4 hours after a dose would significantly reduce the amount of drug ingested by a nursing infant. The American Academy of Pediatrics (AAP) regards nifedipine as usually compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Acute myocardial infarction, bradycardia, cardiogenic shock, coronary artery disease, heart failure, hypotension, ventricular dysfunction

    Nifedipine should be used cautiously in patients with severe bradycardia. It also should be used cautiously in patients with congestive heart failure (or left ventricular dysfunction) because nifedipine can precipitate or exacerbate heart failure due to its negative inotropic effects, particularly in patients receiving concomitant beta-blocker therapy. The development or worsening of pulmonary edema is a marker for discontinuation of nifedipine. The manufacturer of Adalat CC (extended-release nifedipine) states that use in patients in cardiogenic shock is contraindicated. Immediate-release nifedipine should be avoided in certain coronary artery disease states which include cardiogenic shock or acute myocardial infarction (or other acute coronary syndromes such as unstable angina) due to its negative inotropic effects and the reflex sympathetic activation, tachycardia, and hypotension associated with its use. Although immediate-release nifedipine (including sublingual or 'bite and swallow' administration) was frequently used for the treatment of hypertensive urgencies prior to 1995, serious adverse effects have been reported with its use, primarily due to the unpredictable rate and degree of blood pressure lowering. Profound hypotension, myocardial infarction, and death have been reported when immediate-release nifedipine was used to lower blood pressure acutely. Therefore, according to recommendations of the Joint National Committee on Prevention, Detection Evaluation, and Treatment of High Blood Pressure (JNC-VI), nifedipine liquid-filled capsules are contraindicated in the setting of hypertensive urgency, hypertensive crisis, or hypertensive emergency. The routine, sporadic use of nifedipine liquid-filled capsules whenever blood pressure rises above a predetermined level is not considered appropriate. The immediate-release nifedipine dosage form is currently only indicated for the treatment of chronic stable angina or vasospastic angina.

    Geriatric

    The use of nifedipine immediate-release dosage forms in geriatric patients (aged 71 years and older) for the treatment of hypertension has been associated with a nearly 4-fold increase in risk for all-cause mortality when compared to other antihypertensives (beta-blockers, ACE inhibitors, or non-dihydropyridine calcium channel blockers). Nifedipine plasma concentrations are significantly increased in elderly patients. This patient population may be at greater risk for drug accumulation and toxicity; initiate dosage cautiously. Small pharmacokinetic studies have identified an increase in the half-life, Cmax, and AUC in elderly populations. In healthy subjects, the clearance of nifedipine after intravenous administration was decreased by 33% in the elderly compared to younger subjects. These changes are not due to changes in renal function. According to the Beers Criteria, immediate-release nifedipine is considered a potentially inappropriate medication (PIM) in geriatric patients; avoid use due to the potential for hypotension and the risk of precipitating myocardial ischemia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. Calcium channel blockers may cause peripheral edema and clinically significant constipation; some agents may cause generalized aching, headache, and muscle pain. OBRA states that short acting/immediate-release nifedipine increases the risk of cardiac complications and should not be used.

    Aortic stenosis

    Nifedipine should be avoided in patients with advanced aortic stenosis because the drug can worsen the abnormal pressure gradient associated with this condition.

    Colostomy, constipation, diabetes mellitus, diverticulitis, esophageal stricture, gastric cancer, gastroesophageal reflux disease (GERD), GI obstruction, hiatal hernia, hypothyroidism, ileus, inflammatory bowel disease, obesity

    Because calcium channel blockers relax the lower esophageal sphincter, nifedipine should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Nifedipine extended-release formulations have been associated with rare reports of obstructive symptoms in patients with known strictures as well as in patients with no known gastrointestinal disease. In some cases hospitalization and surgical intervention have been necessary. Use caution in patients at increased risk of GI obstruction including those with an alteration in gastrointestinal anatomy such as severe gastrointestinal narrowing (e.g., esophageal stricture), gastric cancer, colon cancer, small bowel obstruction, bowel resection, gastric bypass, vertical banded gastroplasty, colostomy, diverticulitis, diverticulosis, and inflammatory bowel disease), hypomotility disorders (constipation, gastroesophageal reflux disease (GERD), ileus, obesity, hypothyroidism, and diabetes mellitus) and aggravating concomitant medications (H2-histamine blockers, opiate agonists, nonsteroidal anti-inflammatory drugs, laxatives, anticholinergic agents, levothyroxine, and neuromuscular blocking agents).

    Children, infants

    The safety and efficacy of nifedipine use in infants, children, and adolescents has not been established.

    Hepatic disease

    Nifedipine plasma concentrations are significantly increased in patients with hepatic disease such as cirrhosis. These patients may be at greater risk for drug accumulation and toxicity. It is unknown how systemic exposure may be altered in patients with moderate or severe hepatic impairment. Careful monitoring and dose reduction may be necessary; consider initiating therapy with the lowest dose available (see Dosage).

    Lactase deficiency

    According to the manufacturer of Adalat CC, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take nifedipine formulations that contain lactose.

    ADVERSE REACTIONS

    Severe

    heart failure / Delayed / 2.0-6.7
    myocardial infarction / Delayed / 4.0-6.7
    atrial fibrillation / Early / 0-1.0
    arrhythmia exacerbation / Early / 0-1.0
    cardiac arrest / Early / 0-1.0
    bradycardia / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    angioedema / Rapid / 0-1.0
    GI bleeding / Delayed / 0-1.0
    ocular hemorrhage / Delayed / 0-1.0
    visual impairment / Early / 0-1.0
    exfoliative dermatitis / Delayed / 0-0.5
    Stevens-Johnson syndrome / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    bezoar / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 4.0-30.0
    palpitations / Early / 0-7.0
    wheezing / Rapid / 6.0-6.0
    dyspnea / Early / 0-6.0
    hypotension / Rapid / 0-5.0
    constipation / Delayed / 0-3.3
    chest pain (unspecified) / Early / 0-3.0
    impotence (erectile dysfunction) / Delayed / 0-3.0
    blurred vision / Early / 0-2.0
    angina / Early / 0-1.0
    phlebitis / Rapid / 0-1.0
    orthostatic hypotension / Delayed / 0-1.0
    premature ventricular contractions (PVCs) / Early / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    hypertonia / Delayed / 0-1.0
    ataxia / Delayed / 0-1.0
    confusion / Early / 0-1.0
    depression / Delayed / 0-1.0
    migraine / Early / 0-1.0
    gingival hyperplasia / Delayed / 0-1.0
    dysphagia / Delayed / 0-1.0
    esophagitis / Delayed / 0-1.0
    melena / Delayed / 0-1.0
    dysuria / Early / 0-1.0
    nephrolithiasis / Delayed / 0-1.0
    hematuria / Delayed / 0-1.0
    gout / Delayed / 0-1.0
    myasthenia / Delayed / 0-1.0
    amblyopia / Delayed / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    eosinophilia / Delayed / 0-1.0
    lymphadenopathy / Delayed / 0-1.0
    hot flashes / Early / 0-1.0
    leukopenia / Delayed / 0-0.5
    thrombocytopenia / Delayed / 0-0.5
    anemia / Delayed / 0-0.5
    peripheral vasodilation / Rapid / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known

    Mild

    dizziness / Early / 4.0-27.0
    flushing / Rapid / 0-25.0
    headache / Early / 10.0-23.0
    weakness / Early / 10.0-12.0
    nausea / Early / 2.0-11.0
    pyrosis (heartburn) / Early / 11.0-11.0
    tremor / Early / 0-8.0
    muscle cramps / Delayed / 0-8.0
    throat irritation / Early / 6.0-6.0
    cough / Delayed / 0-6.0
    nasal congestion / Early / 0-6.0
    fatigue / Early / 4.0-5.9
    asthenia / Delayed / 0-4.0
    vertigo / Early / 0-3.0
    drowsiness / Early / 0-3.0
    paresthesias / Delayed / 0-3.0
    insomnia / Early / 0-3.0
    epistaxis / Delayed / 0-3.0
    rhinitis / Early / 0-3.0
    rash / Early / 0-3.0
    pruritus / Rapid / 0-3.0
    xerostomia / Early / 0-3.0
    abdominal pain / Early / 0-3.0
    diarrhea / Early / 0-3.0
    dyspepsia / Early / 0-3.0
    flatulence / Early / 0-3.0
    increased urinary frequency / Early / 0-3.0
    polyuria / Early / 0-3.0
    arthralgia / Delayed / 0-3.0
    urticaria / Rapid / 0-2.0
    hyperhidrosis / Delayed / 0-2.0
    chills / Rapid / 0-2.0
    fever / Early / 0-2.0
    syncope / Early / 0-1.0
    libido decrease / Delayed / 0-1.0
    hypoesthesia / Delayed / 0-1.0
    nightmares / Early / 0-1.0
    anxiety / Delayed / 0-1.0
    pharyngitis / Delayed / 0-1.0
    sinusitis / Delayed / 0-1.0
    petechiae / Delayed / 0-1.0
    photosensitivity / Delayed / 0-1.0
    purpura / Delayed / 0-1.0
    alopecia / Delayed / 0-1.0
    gynecomastia / Delayed / 0-1.0
    breast enlargement / Delayed / 0-1.0
    mastalgia / Delayed / 0-1.0
    gastroesophageal reflux / Delayed / 0-1.0
    weight gain / Delayed / 0-1.0
    weight loss / Delayed / 0-1.0
    vomiting / Early / 0-1.0
    dysgeusia / Early / 0-1.0
    eructation / Early / 0-1.0
    pelvic pain / Delayed / 0-1.0
    nocturia / Early / 0-1.0
    myalgia / Early / 0-1.0
    back pain / Delayed / 0-1.0
    diplopia / Early / 0-1.0
    lacrimation / Early / 0-1.0
    tinnitus / Delayed / 0-1.0
    malaise / Early / 0-1.0
    paranoia / Early / 0-0.5

    DRUG INTERACTIONS

    Acebutolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Acetaminophen; Butalbital: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Acetaminophen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Acrivastine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Aldesleukin, IL-2: (Moderate) Calcium channel blockers may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alfentanil: (Moderate) Monitor patients for bradycardia and hypotension when alfentanil is coadministered with nifedipine. Alfentanil may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with alfentanil is increased in patients receiving nifedipine.
    Alfuzosin: (Moderate) The concomitant administration of alpha-blockers with other antihypertensive agents can cause additive hypotensive effects. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Alogliptin; Metformin: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Alogliptin; Pioglitazone: (Minor) Concentrations of nifedipine may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of nifedipine ER was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with nifedipine ER 30 mg once daily for 4 days resulted in a 13% and 17% reduction in nifedipine ER AUC and Cmax, respectively. In addition, coadministration for 7 days resulted in a 5% and 4% increase in pioglitazone AUC and Cmax, respectively. Patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure; nifedipine dosages may need to be adjusted while the patient is receiving pioglitazone. Close monitoring of blood glucose is also recommended; dosage adjustments in pioglitazone may be needed.
    Alprazolam: (Moderate) In patients taking drugs that inhibit CYP3A isoenzymes, use alprazolam with caution and consider alprazolam dose reduction (up to 50% dose reduction may be needed). Niifedipine may theoretically inhibit CYP3A4 metabolism of alprazolam.
    Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, like calcium channel blockers, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Amifostine: (Major) Patients receiving calcium-channel blockers should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped for 24 hours before chemotherapy doses of amifostine, patients should not receive amifostine.
    Aminolevulinic Acid: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Amiodarone: (Moderate) Amiodarone is a CYP3A4 inhibitor, which theoretically may decrease hepatic clearance and enhance oral bioavailability of nifedipine (CYP3A4 substrate).
    Amobarbital: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of clarithromycin and nifedipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving nifedipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Nifedipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin and nifedipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving nifedipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Nifedipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
    Amphetamine; Dextroamphetamine Salts: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Amprenavir: (Moderate) Amprenavir may inhibit the metabolism of medications that are metabolized via CYP3A4. Although drug interaction studies have not been conducted, the serum concentrations of nifedipine may be increased with concomitant administration of amprenavir.
    Amyl Nitrite: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Apalutamide: (Major) Avoid coadministration of nifedipine with apalutamide and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Apomorphine: (Moderate) Use of calcium-channel blockers and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.
    Apraclonidine: (Minor) Apraclonidine had minimal effects on heart rate and blood pressure during clinical studies in patients with glaucoma. However, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Use caution during concurrent use, especially in patients with severe, uncontrolled cardiovascular disease, including hypertension.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if nifedipine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in nifedipine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Nifedipine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of nifedipine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.
    Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Atazanavir: (Moderate) Atazanavir may interact with certain calcium-channel blockers that undergo significant metabolism via CYP3A4, including nifedipine. Cautious dose titration of amlodipine should be considered; the patient should be monitored for the proper clinical responses to calcium-channel blocker therapy.
    Atazanavir; Cobicistat: (Moderate) Atazanavir may interact with certain calcium-channel blockers that undergo significant metabolism via CYP3A4, including nifedipine. Cautious dose titration of amlodipine should be considered; the patient should be monitored for the proper clinical responses to calcium-channel blocker therapy. (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as nifedipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate reductions are advised.
    Atenolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Atenolol; Chlorthalidone: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Avanafil: (Moderate) Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. For example, in patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 3 to 4 mmHg (age group 65 to 69 years) and 5 to 6 mmHg (age group 70 to 80 years) compared to placebo.
    Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Barbiturates: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Bendroflumethiazide; Nadolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Benzonatate: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Benzphetamine: (Minor) Benzphetamine might increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Beta-blockers: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Betaxolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Bisoprolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Bortezomib: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
    Bosentan: (Moderate) Closely monitor blood pressure if coadministration of nifedipine with bosentan is necessary; decreased plasma concentrations of nifedipine may occur. Nifedipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
    Brimonidine; Timolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Brompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Butabarbital: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Canagliflozin; Metformin: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Carbamazepine: (Major) Avoid coadministration of nifedipine with carbamazepine and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and carbamazepine is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbetapentane; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Carbinoxamine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Carbinoxamine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Carbonic anhydrase inhibitors: (Moderate) Nifedipine can have additive hypotensive effects with other antihypertensive agents (including carbonic anhydrase inhibitors). This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Carteolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Carvedilol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Celecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ceritinib: (Moderate) Monitor blood pressure if coadministration of nifedipine with ceritinib is necessary; consider decreasing the dose of nifedipine if appropriate. Nifedipine is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Concomitant use may increase nifedipine exposure.
    Cetirizine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Chlorpheniramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Chlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Cimetidine: (Moderate) Cimetidine has been shown to increase the oral bioavailability of dihydropyridines. Cimetidine can potentially affect the disposition of nifedipine due to inhibitory effects on cytochrome P-450 and, therefore, first-pass metabolism of nifedipine, increasing nifedipine bioavailability and serum concentrations. Lower doses of nifedipine may be considered during concomitant therapy with cimetidine.
    Cisapride: (Moderate) Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine.
    Clarithromycin: (Major) Avoid coadministration of clarithromycin and nifedipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving nifedipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure closely. Nifedipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8).
    Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Cobicistat: (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as nifedipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate reductions are advised.
    Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
    Codeine; Phenylephrine; Promethazine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Conivaptan: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor, and nifedipine, a CYP3A4 substrate. Coadministration may result in elevated nifedipine plasma concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4, such as nifedipine, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension. Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
    Crizotinib: (Moderate) Monitor for an increase in nifedipine-related adverse reactions, including hypotension, if coadministration with crizotinib is necessary. Nifedipine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
    Cyclosporine: (Moderate) Cyclosporine may increase nifedipine blood concentrations when given concomitantly. Concurrent use of cyclosporine and nifedipine has been associated with increased severity and frequency of gingival hyperplasia; patients receiving these drugs together should be instructed to follow strict oral hygiene. Patients with severe gingival hyperplasia should be promptly referred for evaluation. Nifedipine has been shown to have minimal effects on cyclosporine blood concentrations.
    Danazol: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates like calcium-channel blockers.
    Dantrolene: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Dapagliflozin; Metformin: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Darunavir: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Nifedipine undergoes significant metabolism via CYP3A4 and increased plasma concentrations would be expected with coadministration. Cautious dose titration of calcium-channel blockers should be considered; the patient should be monitored for the proper clinical responses to calcium-channel blocker therapy.
    Darunavir; Cobicistat: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Nifedipine undergoes significant metabolism via CYP3A4 and increased plasma concentrations would be expected with coadministration. Cautious dose titration of calcium-channel blockers should be considered; the patient should be monitored for the proper clinical responses to calcium-channel blocker therapy. (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as nifedipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate reductions are advised.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Nifedipine undergoes significant metabolism via CYP3A4 and increased plasma concentrations would be expected with coadministration. Cautious dose titration of calcium-channel blockers should be considered; the patient should be monitored for the proper clinical responses to calcium-channel blocker therapy. (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as nifedipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate reductions are advised.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) According to the manufacturer of nifedipine, coadministration with ritonavir may result in increased exposure to nifedipine, and initiation of nifedipine should begin with the lowest available dose. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as nifedipine, should be expected with concurrent use of delavirdine.
    Desloratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Dexmedetomidine: (Moderate) Concomitant administration of dexmedetomidine and calcium-channel blockers could lead to additive hypotension and bradycardia; use together with caution. Dexmedetomidine can produce bradycardia or AV block and should be used cautiously in patients who are receiving antihypertensive drugs that may lower the heart rate such as calcium-channel blockers.
    Dexmethylphenidate: (Moderate) Dexmethylphenidate can reduce the hypotensive effect of antihypertensive agents, including calcium-channel blockers. Periodic evaluation of blood pressure is advisable during concurrent use of dexmethylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of dexmethylphenidate.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Dextromethorphan; Quinidine: (Moderate) Nifedipine has been reported to rarely decrease quinidine serum concentrations. Quinidine concentrations may decrease by 20% to 40% when nifedipine is added, and potentially increase after nifedipine is withdrawn. There have also been reports of no significant change in quinidine concentrations or effect. In addition, both drugs can cause hypotension, and these effects can be additive. Careful monitoring of serum quinidine concentrations is prudent following the addition or discontinuation of nifedipine, with dose adjustment as clinically warranted. Monitor heart rate, blood pressure, and cardiac response.
    Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents.
    Diclofenac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diclofenac; Misoprostol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diethylpropion: (Major) Diethylpropion has vasopressor effects and may limit the benefit of calcium-channel blockers. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
    Diflunisal: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Digoxin: (Major) Measure serum digoxin concentrations before initiating nifedipine. If necessary, reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Coadministration of digoxin and nifedipine increases the serum concentration of digoxin by 45%. This is believed to be due to decreased renal and nonrenal clearance of digoxin by nifedipine.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Diltiazem: (Moderate) Diltiazem has been reported to increase the plasma level and hypotensive effects of nifedipine via CYP3A4 inhibition.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Diphenhydramine; Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diphenhydramine; Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diphenhydramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Disopyramide: (Major) Nifedipine has some potential to reduce cardiac contractility. Use caution when administering concomitantly with other agents known to affect cardiac contractility and/or conduction such as disopyramide.
    Dorzolamide; Timolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Dronedarone: (Moderate) Monitor for an increase in nifedipine-related adverse reactions, including hypotension, if coadministration with dronedarone is necessary. Nifedipine is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor.
    Drospirenone; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
    Dutasteride; Tamsulosin: (Moderate) The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Efavirenz: (Moderate) Use caution and careful monitoring when coadministering efavirenz with certain calcium-channel blockers. Efavirenz induces CYP3A4, potentially altering serum concentrations of calcium-channel blockers metabolized via CYP3A4. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments are made based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, lercanidipine, nicardipine, and verapamil); adjust based on clinical response.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Use caution and careful monitoring when coadministering efavirenz with certain calcium-channel blockers. Efavirenz induces CYP3A4, potentially altering serum concentrations of calcium-channel blockers metabolized via CYP3A4. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments are made based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, lercanidipine, nicardipine, and verapamil); adjust based on clinical response.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution and careful monitoring when coadministering efavirenz with certain calcium-channel blockers. Efavirenz induces CYP3A4, potentially altering serum concentrations of calcium-channel blockers metabolized via CYP3A4. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments are made based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, lercanidipine, nicardipine, and verapamil); adjust based on clinical response.
    Elbasvir; Grazoprevir: (Moderate) Administering nifedipine with elbasvir; grazoprevir may result in elevated nifedipine plasma concentrations. Nifedipine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Use caution when administering ivacaftor and nifedipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as nifedipine, can increase nifedipine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as nifedipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate reductions are advised.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as nifedipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate reductions are advised.
    Empagliflozin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Empagliflozin; Linagliptin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
    Empagliflozin; Metformin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control. (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Enflurane: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Enzalutamide: (Major) Avoid coadministration of nifedipine with enzalutamide, and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and enzalutamide is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Ephedrine: (Major) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by calcium-channel blockers. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Epirubicin: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
    Eplerenone: (Moderate) Nifedipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Epoprostenol: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Ergonovine: (Major) Because of its potential to cause coronary vasospasm, ergonovine could theoretically antagonize the therapeutic effects of anti-anginal agents including calcium-channel blockers. In addition, calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, and verapamil, may also reduce the hepatic metabolism of ergonovine and increase the risk of ergot toxicity.
    Ertugliflozin; Metformin: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Erythromycin: (Major) Avoid administration of erythromycin and nifedipine, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving nifedipine therapy. If coadministration is unavoidable, monitor blood pressure and heart rate. Nifedipine is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor.
    Erythromycin; Sulfisoxazole: (Major) Avoid administration of erythromycin and nifedipine, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving nifedipine therapy. If coadministration is unavoidable, monitor blood pressure and heart rate. Nifedipine is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor.
    Esmolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Esomeprazole; Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal therapy should be monitored for antihypertensive effectiveness.
    Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal therapy should be monitored for antihypertensive effectiveness.
    Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Desogestrel: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Etonogestrel: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norelgestromin: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestimate: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Ethinyl Estradiol; Norgestrel: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Etodolac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Etomidate: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Famotidine; Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Fedratinib: (Moderate) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with fedratinib as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
    Fenoprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Fentanyl: (Moderate) Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta-blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine-treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient's condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery.
    Fexofenadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Flecainide: (Major) Because both flecainide and nifedipine have negative inotropic properties, additive effects are possible especially in patients with abnormal ventricular function. Per the manufacturer of flecainide, concomitant use with nifedipine is not recommended until more data is available.
    Fluconazole: (Moderate) Fluconazole may decrease the clearance of calcium-channel blockers, including nifedipine, via inhibition of CYP3A4 metabolism. Consider initiating nifedipine therapy with the lowest available dose if coadminstered with fluconazole. Monitor blood pressure closely during concurrent use of these medications.
    Fluoxetine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including nifedipine, via inhibition of CYP3A4 metabolism.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including nifedipine, via inhibition of CYP3A4 metabolism. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Flurbiprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Fosamprenavir: (Moderate) Fosamprenavir may inhibit the metabolism of other medications that are metabolized via CYP3A4. Although drug interaction studies have not been conducted, the serum concentrations of nifedipine may be increased with concomitant administration of fosamprenavir.
    Fosphenytoin: (Major) Avoid coadministration of nifedipine with fosphenytoin and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Fospropofol: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Gallium Ga 68 Dotatate: (Moderate) Nifedipine can have additive hypotensive effects with other antihypertensive agents (including diuretics). This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    General anesthetics: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Ginkgo, Ginkgo biloba: (Moderate) Ginkgo biloba appears to inhibit the metabolism of calcium-channel blockers, perhaps by inhibiting the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that the concurrent administration of ginkgo with nifedipine resulted in a 53% increase in nifedipine peak concentrations. More study is needed regarding ginkgo's effects on CYP3A4 and whether clinically significant drug interactions result.
    Ginseng, Panax ginseng: (Moderate) Ginseng appears to inhibit the metabolism of calcium-channel blockers, perhaps by inhibiting the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that the concurrent administration of ginseng with nifedipine resulted in a 30% increase in nifedipine peak concentrations. More study is needed regarding ginseng's effects on CYP3A4 and whether clinically significant drug interactions result.
    Glimepiride; Pioglitazone: (Minor) Concentrations of nifedipine may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of nifedipine ER was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with nifedipine ER 30 mg once daily for 4 days resulted in a 13% and 17% reduction in nifedipine ER AUC and Cmax, respectively. In addition, coadministration for 7 days resulted in a 5% and 4% increase in pioglitazone AUC and Cmax, respectively. Patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure; nifedipine dosages may need to be adjusted while the patient is receiving pioglitazone. Close monitoring of blood glucose is also recommended; dosage adjustments in pioglitazone may be needed.
    Glipizide; Metformin: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Glyburide; Metformin: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Grapefruit juice: (Major) Clinicians should be aware that grapefruit juice (food) interactions with some calcium channel blockers are possible. Grapefruit juice contains compounds (psoralen derivatives and possibly the flavonoid naringenin) that inhibit the cytochrome P-450 CYP3A4 isozyme in the gut wall. Grapefruit juice can increase the serum concentrations and oral bioavailability of some of the calcium-channel blockers (e.g., felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, and verapamil); no significant effect on diltiazem bioavailability has been reported. Coadministration of oral nifedipine with grapefruit juice increases the AUC and peak plasma concentrations of nifedipine by 2-fold, with no change in half-life. The increase in nifedipine bioavailability is most likely due to inhibition of the CYP3A4 isoenzyme, resulting in reduced first-pass drug metabolism. To avoid increased drug bioavailability, it is generally recommended to avoid grapefruit juice before or after nifedipine administration. The manufacturer for Adalat CC recommends stopping grapefruit juice for 3 days prior to initiating nifedipine therapy.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Haloperidol: (Moderate) In general, antipsychotics like haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension.
    Halothane: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Hawthorn, Crataegus laevigata: (Moderate) Hawthorn, Crataegus laevigata (also known as C. oxyacantha) may potentially interact with antihypertensive, heart failure, or arrhythmia medications such as the calcium-channel blockers. Following hawthorn administration, the cardiac action potential duration is increased and the refractory period is prolonged. Hawthorn may also lower peripheral vascular resistance. Patients with hypertension or heart failure should be advised to only use hawthorn with their prescribed medications after discussion with their prescriber. Patients who choose to take hawthorn should receive periodic blood pressure and heart rate monitoring.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Hydrocodone; Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Hydrocodone; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ibuprofen; Oxycodone: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ibuprofen; Pseudoephedrine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Idelalisib: (Major) Avoid coadministration of nifedipine with idelalisib and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and idelalisib is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Iloprost: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Imatinib: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including nifedipine.
    Indinavir: (Moderate) According to the manufacturer of nifedipine, coadministration with indinavir may result in increased exposure to nifedipine, and initiation of nifedipine should begin with the lowest available dose. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Indocyanine Green: (Moderate) In a study of 9 healthy adults given 0.5 mg/kg of indocyanine green, nifedipine increased indocyanine green clearance by 14%.
    Indomethacin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with nifedipine may result in increased serum concentrations of nifedipine. Nifedipine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Isoflurane: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of nifedipine with rifampin, and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and rifampin is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of nifedipine with rifampin, and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and rifampin is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Isoproterenol: (Moderate) The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
    Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Isosorbide Mononitrate: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Itraconazole: (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase nifedipine serum concentrations via inhibition of CYP3A4 with the potential for nifedipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and dihydropyridine calcium-channel blockers; therefore, caution is recommended when administering these medication in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and nifedipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as nifedipine, can increase nifedipine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ketamine: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Ketoconazole: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, such as nifedipine, via inhibition of CYP3A4 metabolism.
    Ketoprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ketorolac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Labetalol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as calcium-channel blockers, because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    Lanreotide: (Moderate) Concomitant administration of bradycardia-inducing drugs (e.g., calcium-channel blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Adjust the calcium-channel blocker dose if necessary.
    Lansoprazole; Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Lefamulin: (Moderate) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with oral lefamulin as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of nifedipine; monitor for potential reduction in efficacy. Nifedipine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of nifedipine; monitor for potential reduction in efficacy. Nifedipine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) Closely monitor for nifedipine-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of nifedipine, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Levobetaxolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Levobunolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Linagliptin; Metformin: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Lisdexamfetamine: (Minor) Lisdexamfetamine might increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Lithium: (Moderate) Lithium neurotoxicity has been reported during co-administration of lithium and verapamil or diltiazem, and is possible during concurrent use of other calcium-channel blockers with lithium. Symptoms of toxicity have included ataxia, tremors, nausea, vomiting, diarrhea, and tinnitus. The interaction between verapamil and lithium is variable and unpredictable. Both decreased lithium concentrations and lithium toxicity have been reported after the addition of verapamil. The possibility of a loss of lithium's therapeutic effect due to lower serum lithium concentrations may be offset somewhat by the fact that calcium-channel blocking agents share some neuropharmacological actions with lithium; limited data suggest that oral verapamil is effective in controlling an acute manic episode either as a single agent or in combination with lithium. Regarding diltiazem, although neurotoxicity was reported after the addition of diltiazem, other drugs were administered concomitantly. Worsened psychosis has been reported with the combination of diltiazem and lithium. Until more data are available, diltiazem and verapamil should be used cautiously in patients receiving lithium.
    Lopinavir; Ritonavir: (Major) According to the manufacturer of nifedipine, coadministration with ritonavir may result in increased exposure to nifedipine, and initiation of nifedipine should begin with the lowest available dose. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. (Major) Lopinavir; ritonavir (Kaletra) may decrease the clearance of calcium-channel blockers via inhibition of CYP3A4 metabolism. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of lopinavir; ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. Caution is warranted and clinical monitoring of the patient is recommended.
    Loratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of nifedipine and lumacaftor; ivacaftor and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and nifedipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as nifedipine, can increase nifedipine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Magnesium: (Major) Clinically significant drug interactions including neuromuscular blockade and hypotension have occurred when IV magnesium salts were given concurrently with nifedipine during the treatment of hypertension or premature labor during pregnancy. The effects have been attributed to nifedipine potentiation of the neuromuscular blocking effects of magnesium. It is recommended that nifedipine not be given concurrently with magnesium therapy for pre-eclampsia, hypertension, or tocolytic treatment during pregnancy.
    Mannitol: (Moderate) Nifedipine can have additive hypotensive effects with other antihypertensive agents (including diuretics). This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Maraviroc: (Minor) Use caution and careful monitoring with the coadministration of maraviroc and nifedipine as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (Pgp); nifedipine is a mild inhibitor of Pgp. The effects of Pgp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Meclofenamate Sodium: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Mefenamic Acid: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Melatonin: (Moderate) Melatonin may impair the efficacy of some calcium-channel blockers, and caution is advised with concurrent use. In one placebo-controlled study, melatonin evening ingestion led to significant increases in blood pressure (6.5 mmHg systolic and 4.9 mmHg diastolic) and heart rate (3.9 bpm) throughout the day in patients taking nifedipine (GITS formulation). Melatonin appeared to antagonize the antihypertensive effects of nifedipine. The mechanism of this interaction is unclear. It may be prudent to avoid melatonin use during calcium-channel blocker therapy.
    Meloxicam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Mephobarbital: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    Metformin: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Metformin; Pioglitazone: (Minor) Concentrations of nifedipine may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of nifedipine ER was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with nifedipine ER 30 mg once daily for 4 days resulted in a 13% and 17% reduction in nifedipine ER AUC and Cmax, respectively. In addition, coadministration for 7 days resulted in a 5% and 4% increase in pioglitazone AUC and Cmax, respectively. Patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure; nifedipine dosages may need to be adjusted while the patient is receiving pioglitazone. Close monitoring of blood glucose is also recommended; dosage adjustments in pioglitazone may be needed. (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Metformin; Repaglinide: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Metformin; Rosiglitazone: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Metformin; Saxagliptin: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Metformin; Sitagliptin: (Minor) Nifedipine may increase the plasma metformin Cmax and AUC and increase the amount of metformin excreted in the urine. Metformin half-life is unaffected. Nifedipine appears to enhance the absorption of metformin.
    Methamphetamine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Methohexital: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Methoxsalen: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylphenidate: (Minor) Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate. Methylphenidate can reduce the hypotensive effect of antihypertensive agents, including calcium-channel blockers.
    Methysergide: (Major) Because of the potential to cause coronary vasospasm , methysergide theoretically could antagonize the therapeutic effects of calcium-channel blockers. Clinicians should also note that calcium-channel blockers with CYP3A4 inhibitory properties, such as diltiazem, nicardipine, verapamil, may also reduce the hepatic metabolism of selected ergot alkaloids and increase the risk of ergot toxicity.
    Metoprolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Micafungin: (Moderate) Concomitant nifedipine and micafungin administration may increase the systemic exposure and the maximum serum concentration of nifedipine. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state micafungin compared with nifedipine alone. Patients should be monitored closely for nifedipine-related side effects; nifedipine dosage reduction may be necessary.
    Mifepristone: (Moderate) Monitor blood pressure and heart rate if coadministration of nifedipine with mifepristone is necessary. Concurrent use may result in elevated nifedipine concentrations. Nifedipine is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mitotane: (Major) Avoid coadministration of nifedipine and mitotane and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Moricizine: (Major) Nifedipine has negative inotropic properties and it may be prudent to monitor patients closely if nifedipine is used with other drugs that are negative inotropes such as moricizine.
    Nabumetone: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Nadolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Nanoparticle Albumin-Bound Paclitaxel: (Minor) Additive bradycardia may occur in patients receiving paclitaxel and other drugs known to cause bradycardia, such as calcium-channel blockers like nifedipine. These patients may require additional monitoring and information.
    Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Naproxen; Pseudoephedrine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Naproxen; Sumatriptan: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Nebivolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Nebivolol; Valsartan: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Nefazodone: (Moderate) Nefazodone is a CYP3A4 inhibitor which theoretically may decrease hepatic clearance and enhance oral bioavailability of nifedipine, a CYP3A4 substrate. In addition, although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary.
    Nelfinavir: (Moderate) According to the manufacturer of nifedipine, coadministration with nelfinavir may result in increased exposure to nifedipine, and initiation of nifedipine should begin with the lowest available dose. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. If coadministration is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Nevirapine: (Minor) Nevirapine is an inducer of the cytochrome P4503A enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme, including calcium-channel blockers may require dosage adjustments.
    Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Nitrates: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Nitroglycerin: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
    Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Nonsteroidal antiinflammatory drugs: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Octreotide: (Moderate) Dose adjustments in drugs such as beta-blockers and calcium-channel blockers which cause bradycardia and/or affect cardiac conduction may be necessary during octreotide therapy due to additive effects.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) According to the manufacturer of nifedipine, coadministration with ritonavir may result in increased exposure to nifedipine, and initiation of nifedipine should begin with the lowest available dose. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Oritavancin: (Moderate) Nifedipine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of nifedipine may be reduced if these drugs are administered concurrently.
    Oxaprozin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by calcium-channel blockers. If these drugs are used together, closely monitor for changes in blood pressure.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and calcium-channel blockers who are susceptible to hypotension.
    Pasireotide: (Major) Pasireotide may cause a decrease in heart rate. Closely monitor patients who are also taking drugs associated with bradycardia such as calcium-channel blockers. Dose adjustments of calcium-channel blockers may be necessary.
    Penbutolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Pentobarbital: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Phenobarbital: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Phenylephrine; Promethazine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Phenytoin: (Major) Avoid coadministration of nifedipine with phenytoin and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Phosphodiesterase inhibitors: (Moderate) Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. For example, in patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 3 to 4 mmHg (age group 65 to 69 years) and 5 to 6 mmHg (age group 70 to 80 years) compared to placebo.
    Photosensitizing agents (topical): (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Photosensitizing agents: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Pindolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Pioglitazone: (Minor) Concentrations of nifedipine may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of nifedipine ER was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with nifedipine ER 30 mg once daily for 4 days resulted in a 13% and 17% reduction in nifedipine ER AUC and Cmax, respectively. In addition, coadministration for 7 days resulted in a 5% and 4% increase in pioglitazone AUC and Cmax, respectively. Patients should be monitored for the desired cardiovascular effects on heart rate, chest pain, or blood pressure; nifedipine dosages may need to be adjusted while the patient is receiving pioglitazone. Close monitoring of blood glucose is also recommended; dosage adjustments in pioglitazone may be needed.
    Piroxicam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Posaconazole: (Moderate) Monitor blood pressure and heart rate if coadministration of nifedipine with posaconazole is necessary. Concurrent use may result in elevated nifedipine concentrations. Nifedipine is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor.
    Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used. The use of alpha-blockers with verapamil can lead to excessive hypotension; In addition, verapamil has been reported to increase the AUC and Cmax of prazosin.
    Primidone: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
    Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Propafenone: (Major) Because both propafenone and nifedipine have negative inotropic properties, additive effects are possible especially in patients with abnormal ventricular function. It may be prudent to monitor patients closely if nifedipine is used with other drugs that are negative inotropes such as propafenone.
    Propofol: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Propranolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
    Quinidine: (Moderate) Nifedipine has been reported to rarely decrease quinidine serum concentrations. Quinidine concentrations may decrease by 20% to 40% when nifedipine is added, and potentially increase after nifedipine is withdrawn. There have also been reports of no significant change in quinidine concentrations or effect. In addition, both drugs can cause hypotension, and these effects can be additive. Careful monitoring of serum quinidine concentrations is prudent following the addition or discontinuation of nifedipine, with dose adjustment as clinically warranted. Monitor heart rate, blood pressure, and cardiac response.
    Ranitidine: (Moderate) Cimetidine can increase nifedipine exposure by inhibiting hepatic metabolism of nifedipine. Ranitidine has been shown to have a similar, but lesser, effect on nifedipine pharmacokinetics. Clinicians should be alert for exaggerated nifedipine effects if ranitidine is coadministered.
    Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider during concurrent use of an MAOI and a calcium-channel blocker.
    Remifentanil: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving calcium-channel blockers due to additive hypotensive effects.
    Ribociclib: (Moderate) Monitor blood pressure if coadministration of nifedipine with ribociclib is necessary; consider decreasing the dose of nifedipine if appropriate. Nifedipine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Concomitant use may increase nifedipine exposure.
    Ribociclib; Letrozole: (Moderate) Monitor blood pressure if coadministration of nifedipine with ribociclib is necessary; consider decreasing the dose of nifedipine if appropriate. Nifedipine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Concomitant use may increase nifedipine exposure.
    Rifabutin: (Severe) Nifedipine is a substrate of the CYP3A4 isoenzyme and its use is contraindicated with potent inducers of CYP3A4, such as rifabutin. Potent CYP3A4 inducers reduce the bioavailability and efficacy of nifedipine.
    Rifampin: (Major) Avoid coadministration of nifedipine with rifampin, and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and rifampin is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Rifapentine: (Severe) Nifedipine is a substrate of CYP3A4 and its use is contraindicated with potent inducers of CYP3A4, such as rifapentine. Potent CYP3A4 inducers reduce the bioavailability and efficacy of nifedipine.
    Risperidone: (Moderate) Risperidone has been associated with orthostatic hypotension and may enhance the hypotensive effects of antihypertensive agents. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medications. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Ritonavir: (Major) According to the manufacturer of nifedipine, coadministration with ritonavir may result in increased exposure to nifedipine, and initiation of nifedipine should begin with the lowest available dose. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Rofecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Saquinavir: (Moderate) According to the manufacturer of nifedipine, coadministration with saquinavir may result in increased exposure to nifedipine, and initiation of nifedipine should begin with the lowest available dose. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. If coadministration is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Secobarbital: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
    Selegiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
    Sevoflurane: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
    Sildenafil: (Moderate) Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. For example, in patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 3 to 4 mmHg (age group 65 to 69 years) and 5 to 6 mmHg (age group 70 to 80 years) compared to placebo.
    Silodosin: (Moderate) Monitor for adverse effects if silodosin is coadministered with nifedipine. The incidence of dizziness and orthostatic hypotension were increased in patients also receiving antihypertensive medications in clinical trials.
    Simeprevir: (Moderate) Coadministration of nifedipine with simeprevir, an inhibitor of intestinal CYP3A4, may result in increased nifedipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by calcium-channel blockers. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of results.
    Sotalol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of nifedipine and St. John's Wort, Hypericum perforatum, and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Sufentanil: (Moderate) Monitor patients for bradycardia and hypotension when sufentanil is coadministered with nifedipine. Sufentanil may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with sufentanil is increased in patients receiving nifedipine.
    Sulindac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Tacrolimus: (Moderate) Tacrolimus is metabolized by CYP3A4 isoenzyme. CYP3A4 is the major isoenzyme that metabolizes nifedipine. When coadministered with nifedipine, tacrolimus whole blood trough concentrations are increased. In a retrospective study of liver transplant patients with hypertension, nifedipine decreased the daily and cumulative dosage requirements of tacrolimus by 26%, 29%, and 38% at 3, 6, and 12 months, respectively, compared with the dosage for patients who did not receive nifedipine. It is recommended that tacrolimus blood concentrations be closely monitored when nifedipine and tacrolimus are administered concomitantly.
    Tadalafil: (Moderate) Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. For example, in patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 3 to 4 mmHg (age group 65 to 69 years) and 5 to 6 mmHg (age group 70 to 80 years) compared to placebo.
    Tamsulosin: (Moderate) The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Telithromycin: (Moderate) Telithromycin, a ketolide antibiotic, can theoretically compete with nifedipine for metabolism by CYP3A4. This can result in increased concentrations of nifedipine if the two drugs are coadministered.
    Temsirolimus: (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with nifedipine; an increase in temsirolimus-related adverse reactions may also occur. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with another calcium channel blocker.
    Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
    Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and nifedipine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as nifedipine, can increase nifedipine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Thalidomide: (Moderate) Thalidomide and other agents that slow cardiac conduction such as calcium-channel blockers should be used cautiously due to the potential for additive bradycardia.
    Thiopental: (Major) Avoid coadministration of nifedipine with barbiturates and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate, and barbiturates are strong CYP3A4 inducers. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Timolol: (Moderate) In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction. Hypotension and impaired cardiac performance can occur during coadministration of nifedipine with beta-blockers, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. Monitor clinical response during coadministration; adjustment of nifedipine dosage may be needed during concurrent beta-blocker therapy.
    Tipranavir: (Moderate) Tipranavir may interact with certain calcium-channel blockers. Tipranavir may interact with calcium-channel blockers that undergo significant metabolism via CYP3A4, including nifedipine. Cautious dose titration of these calcium-channel blockers should be considered; the patient should be monitored for the proper clinical responses to calcium-channel blocker therapy.
    Tolmetin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Trandolapril; Verapamil: (Moderate) Diltiazem has been reported to increase the plasma level and hypotensive effects of nifedipine via CYP3A4 inhibition. Verapamil may also inhibit CYP3A4 metabolism of nifedipine.
    Tranylcypromine: (Severe) The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated.
    Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Urea: (Moderate) Nifedipine can have additive hypotensive effects with other antihypertensive agents (including diuretics). This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Valdecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Vardenafil: (Moderate) Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. For example, in patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 3 to 4 mmHg (age group 65 to 69 years) and 5 to 6 mmHg (age group 70 to 80 years) compared to placebo.
    Verapamil: (Moderate) Diltiazem has been reported to increase the plasma level and hypotensive effects of nifedipine via CYP3A4 inhibition. Verapamil may also inhibit CYP3A4 metabolism of nifedipine.
    Vincristine Liposomal: (Major) Use caution if coadminsitration of nifedipine is necessary with vincristine and monitor for vincristine toxicity. In a pharmacokinetic study of 26 patients with solid tumors and normal renal and hepatic function, vincristine 2 mg IV was administered alone (n = 14) or with nifedipine 10 mg by mouth three times daily for 3 days before and 7 days after (n = 12). Coadministration of nifedipine significantly increased vincristine AUC (10 +/- 2.91 mcg x min/ml vs 2.9 +/- 0.86 mcg x min/ml; p = < 0.001) and terminal half-life (85.56 +/- 23.51 hours vs 21.72 +/- 9.61 hours; p < 0.05) compared with vincristine alone; additionally, the plasma clearance was significantly reduced in patients treated with nifedipine (309.54 +/- 95.46 vs 985.06 +/- 258.6 ml/min/m2; p < 0.01). The mechanism of this interaction is poorly understood.
    Vincristine: (Major) Use caution if coadminsitration of nifedipine is necessary with vincristine and monitor for vincristine toxicity. In a pharmacokinetic study of 26 patients with solid tumors and normal renal and hepatic function, vincristine 2 mg IV was administered alone (n = 14) or with nifedipine 10 mg by mouth three times daily for 3 days before and 7 days after (n = 12). Coadministration of nifedipine significantly increased vincristine AUC (10 +/- 2.91 mcg x min/ml vs 2.9 +/- 0.86 mcg x min/ml; p = < 0.001) and terminal half-life (85.56 +/- 23.51 hours vs 21.72 +/- 9.61 hours; p < 0.05) compared with vincristine alone; additionally, the plasma clearance was significantly reduced in patients treated with nifedipine (309.54 +/- 95.46 vs 985.06 +/- 258.6 ml/min/m2; p < 0.01). The mechanism of this interaction is poorly understood.
    Voriconazole: (Moderate) Monitor blood pressure and heart rate if coadministration of nifedipine with voriconazole is necessary. Concurrent use may result in elevated nifedipine concentrations. Nifedipine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor.
    Warfarin: (Minor) Concurrent administration of highly protein-bound agents such as nifedipine can theoretically displace warfarin from its binding sites, with potential for increased anticoagulation effects. The manufacturer of nifedipine reports rare cases of increased prothrombin time when nifedipine was administered to patients taking warfarin; the relationship to nifedipine is uncertain.
    Yohimbine: (Moderate) Yohimbine (a selective central alpha 2-adrenoceptor antagonist) can increase blood pressure, and therefore can antagonize the therapeutic action of antihypertensive drugs in general. One study in patients with essential hypertension (n = 25) reported an average rise of 5 mmHg in mean blood pressure and a 66% increase in plasma norepinephrine (NE) concentrations following yohimbine administration (4 x 5.4 mg tablets PO). Use with particular caution in hypertensive patients with high or uncontrolled BP.
    Zafirlukast: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease hepatic clearance and enhance oral bioavailability of nifedipine, a CYP3A4 substrate.
    Zileuton: (Minor) Zileuton is a CYP3A4 inhibitor which theoretically may decrease hepatic clearance and enhance oral bioavailability of nifedipine, a CYP3A4 substrate.
    Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.

    PREGNANCY AND LACTATION

    Pregnancy

    Nifedipine is classified as FDA pregnancy category C. According to the manufacturer, the drug should be used only when its benefits clearly outweigh the risks to the fetus. The manufacturer also notes a report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro.

    Because nifedipine is excreted in human milk, the manufacturer does not recommend breast-feeding during nifedipine therapy. Based off of data from a single mother: infant pair, it has been estimated that the amount of drug that would appear in the breast-milk is < 5% of the maternal therapeutic dose. However, neonatal myocardium is very sensitive to changes in calcium status, and the therapeutic dose for a neonate is unknown. The authors further concluded that delaying breast-feeding or expressing milk for 3—4 hours after a dose would significantly reduce the amount of drug ingested by a nursing infant. The American Academy of Pediatrics (AAP) regards nifedipine as usually compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Like other calcium-channel antagonists, nifedipine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores, which are selective for specific ions. Serum calcium levels remain unchanged. It is believed that nifedipine inhibits this influx by physically plugging the channel. While verapamil and diltiazem exert balanced effects on calcium channels in the SA node, AV node, and vasculature, nifedipine and other members of the dihydropyridine group act predominantly on the vasculature, making these agents more potent peripheral vasodilators. The decrease in intracellular calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries. This results in increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.Although these drugs originally were believed to improve oxygen supply, it now appears that their effectiveness as anti-ischemic agents arises from their ability to alter the systemic balance between supply and demand. Reduced afterload and reduced myocardial wall tension lead to reduced myocardial oxygen demand, which now seems to best explain the benefit of nifedipine and other dihydropyridines in the treatment of angina. Thus, nifedipine increases myocardial oxygen supply (secondary to coronary vasodilation) and decreases myocardial oxygen demand (secondary to decreased afterload). Nifedipine appears particularly effective in treating variant angina (i.e., vasospastic angina) due to this ability to increase myocardial oxygen supply by inducing coronary vasodilation. The effectiveness of nifedipine in treating chronic stable angina, on the other hand, is related to the decrease in myocardial oxygen demand secondary to decreased afterload.Nifedipine has no clinical effect on AV conduction, which may be due to its inhibition of phosphodiesterase. This intracellular mechanism of nifedipine actually enhances calcium inflow and counteracts its own inhibitory effects on calcium influx at the membrane surface. Also, phosphodiesterase inhibition causes additional relaxation of vascular smooth muscle. Thus, nifedipine is more potent than verapamil as a peripheral vasodilator but has negligible effects on AV nodal conduction. Negative inotropic effects rarely are noted clinically, presumably due to a reflex increase in heart rate in response to nifedipine's vasodilatory activity. Nifedipine therapy usually does not affect cardiovascular parameters in patients with normal ventricular function, but patients with decreased left ventricular function can experience an increase in ejection fraction and a decrease in left ventricular filling pressures. In general, calcium-channel blockers exert favorable effects on LVH, and do not worsen insulin resistance or exert detrimental effects on the lipid profile.

    PHARMACOKINETICS

    Nifedipine is administered orally and sublingually. It is relatively well distributed, including into breast milk. Nifedipine is protein-bound in a concentration-dependent way, ranging from 92% to 98%. Hepatic metabolism is rapid and complete, causing the formation of 2 inactive metabolites that, along with the parent drug, are excreted primarily in the urine and, to a lesser extent, the feces. Less than 5% is eliminated as unchanged drug. The elimination half-life of nifedipine is approximately 2 to 5 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
    Nifedipine is a CYP3A4 substrate, and its metabolism may be affected by CYP3A4 inhibitors or inducers.

    Oral Route

    Nifedipine is rapidly and well absorbed (90%) following an oral dose but undergoes extensive first-pass metabolism, resulting in a bioavailability of 50% to 70%. The bioavailability of the sustained-release tablet ("gastrointestinal therapeutic system [GITS]") relative to the capsule is 86% after chronic administration. The bioavailability of nifedipine does not appear to be affected by food. Co-administration of nifedipine with grapefruit juice increases the AUC and peak plasma concentrations of nifedipine by 2-fold, with no change in half-life. Bioavailability is substantially increased (up to a 100% increase) in the presence of hepatic impairment. Decreases in gastrointestinal transit time can significantly alter the absorption characteristics of the sustained-release formulation in a relatively unpredictable fashion by increasing the time available for the osmotically driven release to occur.
     
    Sublingual administration of nifedipine liquid (expressed from regular-release capsules) to achieve rapid decreases in blood pressure, such as in the case of hypertensive urgency, has generated much controversy and confusion and is not recommended. There is little difference in the bioavailability when nifedipine capsules are swallowed whole or if they are bitten and swallowed, or bitten and held sublingually. Biting through the capsule does, however, result in slightly earlier plasma concentrations (within 10 minutes) than if capsules were swallowed intact.
     
    Onset of hypotensive effects occurs in 30 minutes to 1 hour after administration of regular-release capsules, with peak effects occurring within 30 minutes to 2 hours. With the sustained-release tablet, serum concentrations do not peak for 6 hours, and hypotensive effects are correspondingly delayed. Duration of pharmacodynamic activity for the immediate-release preparation is approximately 8 hours. The extended-release tablet is designed to release nifedipine continuously in a zero-order process. Once-daily dosing is possible with this dosage form.