Author: druginteractionchecker_lgaiz4

DRUG INTERACTIONS

7 •Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents.

(7.1) •CYP2D6 Inhibitors are likely to increase metoprolol concentration.

(7.2) •Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia.

(7.3) •Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine.

(7.3) 7.1 Catecholamine Depleting Drugs Catecholamine depleting drugs (eg, reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents.

Observe patients treated with TOPROL-XL plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

7.2 CYP2D6 Inhibitors Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration.

In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg and immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life.

In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d.

with immediate-release metoprolol 50 mg t.i.d.

resulted in two- to five-fold increases in the steady-state concentration of metoprolol.

These increases in plasma concentration would decrease the cardioselectivity of metoprolol.

7.3 Digitalis, Clonidine, and Calcium Channel Blockers Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate.

Concomitant use with beta blockers can increase the risk of bradycardia.

If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine.

If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped [see Warnings and Precautions (5.11) ].

DRUG INTERACTIONS

Drug Interactions ACE-Inhibitors and Angiotensin II Antagonists Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists.

These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists.

In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.

Therefore, monitor renal function periodically in patients receiving ACEIs or AIIAs and NSAIDs in combination therapy.

Acetaminophen Acetaminophen had no effect on the plasma levels of sulindac or its sulfide metabolite.

Aspirin The concomitant administration of aspirin with sulindac significantly depressed the plasma levels of the active sulfide metabolite.

A double-blind study compared the safety and efficacy of sulindac tablets 300 or 400 mg daily given alone or with aspirin 2.4 g/day for the treatment of osteoarthritis.

The addition of aspirin did not alter the types of clinical or laboratory adverse experiences for sulindac tablets; however, the combination showed an increase in the incidence of gastrointestinal adverse experiences.

Since the addition of aspirin did not have a favorable effect on the therapeutic response to sulindac tablets, the combination is not recommended.

Cyclosporine Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin.

NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.

Diflunisal The concomitant administration of sulindac tablets and diflunisal in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.

Diuretics Clinical studies, as well as post marketing observations, have shown that sulindac tablets can reduce the natriuretic effect of furosemide and thiazides in some patients.

This response has been attributed to inhibition of renal prostaglandin synthesis.

During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see ), as well as to assure diuretic efficacy.

WARNINGS, Renal Effects DMSO DMSO should not be used with sulindac.

Concomitant administration has been reported to reduce the plasma levels of the active sulfide metabolite and potentially reduce efficacy.

In addition, this combination has been reported to cause peripheral neuropathy.

Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance.

The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%.

These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID.

Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices.

This may indicate that they could enhance the toxicity of methotrexate.

Caution should be used when NSAIDs are administered concomitantly with methotrexate.

NSAIDs The concomitant use of sulindac tablets with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy.

Oral anticoagulants Although sulindac and its sulfide metabolite are highly bound to protein, studies in which sulindac tablets were given at a dose of 400 mg daily have shown no clinically significant interaction with oral anticoagulants.

However, patients should be monitored carefully until it is certain that no change in their anticoagulant dosage is required.

Special attention should be paid to patients taking higher doses than those recommended and to patients with renal impairment or other metabolic defects that might increase sulindac blood levels.

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

Oral hypoglycemic agents Although sulindac and its sulfide metabolite are highly bound to protein, studies in which sulindac tablets were given at a dose of 400 mg daily, have shown no clinically significant interaction with oral hypoglycemic agents.

However, patients should be monitored carefully until it is certain that no change in their hypoglycemic dosage is required.

Special attention should be paid to patients taking higher doses than those recommended and to patients with renal impairment or other metabolic defects that might increase sulindac blood levels.

Probenecid Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma levels of sulindac and sulfone were increased.

Sulindac was shown to produce a modest reduction in the uricosuric action of probenecid, which probably is not significant under most circumstances.

Propoxyphene hydrochloride Propoxyphene hydrochloride had no effect on the plasma levels of sulindac or its sulfide metabolite.

DRUG INTERACTIONS

Drug Interactions Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to Levothyroxine Sodium Tablets, USP.

In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and action of other drugs.

A listing of drug-thyroidal axis interactions is contained in Table 2.

The list of drug-thyroidal axis interactions in Table 2 may not be comprehensive due to the introduction of new drugs that interact with the thyroidal axis or the discovery of previously unknown interactions.

The prescriber should be aware of this fact and should consult appropriate reference sources (e.g., package inserts of newly approved drugs, medical literature) for additional information if a drug-drug interaction with levothyroxine is suspected.

Table 2: Drug-Thyroidal Axis Interactions Drug or Drug Class Effect Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur Dopamine/Dopamine Agonists Glucocorticoids Octreotide Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).

Drugs that alter thyroid hormone secretion Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients.

The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism.

Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents.

Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.

Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma).

Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation.

Amiodarone may induce hyperthyroidism by causing thyroiditis.

Drugs that may decrease T 4 absorption, which may result in hypothyroidism Antacids – Aluminum & Magnesium Hydroxides – Simethicone Bile Acid Sequestrants – Cholestyramine – Colestipol Calcium Carbonate Cation Exchange Resins – Kayexalate Ferrous Sulfate Orlistat Sucralfate Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.

Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex.

Administer levothyroxine at least 4 hours apart from these agents.

Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.

Drugs that may alter T 4 and T 3 serum transport – but FT 4 concentration remains normal; and, therefore, the patient remains euthyroid Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid Drugs that may cause protein-binding site displacement Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs – Fenamates – Phenylbutazone Salicylates ( > 2 g/day) Administration of these agents with levothyroxine results in an initial transient increase in FT4.

Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid.

Salicylates inhibit binding of T4 and T3 to TBG and transthyretin.

An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.

Drugs that may alter T 4 and T 3 metabolism Drugs that may increase hepatic metabolism, which may result in hypothyroidism Carbamazepine Hydantoins Phenobarbital Rifampin Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements.

Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.

Drugs that may decrease T 4 5′ – deiodinase activity Amiodarone Beta-adrenergic antagonists – (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels.

However, serum T4 levels are usually normal but may occasionally be slightly increased.

In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid.

It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state.

Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels.

However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).

Miscellaneous Anticoagulants (oral) – Coumarin Derivatives – Indandione Derivatives Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants.

Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis.

Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.

Antidepressants – Tricyclics (e.g., Amitriptyline) – Tetracyclics (e.g., Maprotiline) – Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated.

Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.

Antidiabetic Agents – Biguanides – Meglitinides – Sulfonylureas – Thiazolidediones – Insulin Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements.

Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.

Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state.

Therapeutic effect of digitalis glycosides may be reduced.

Cytokines – Interferon-α – Interleukin-2 Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both.

Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment.

Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients.

Interferon-β and -γ have not been reported to cause thyroid dysfunction.

Growth Hormones – Somatrem – Somatropin Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure.

However, untreated hypothyroidism may interfere with growth response to growth hormone.

Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.

Methylxanthine Bronchodilators – (e.g., Theophylline) Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.

Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.

Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone.

Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.

Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Oral anticoagulants – Levothyroxine increases the response to oral anticoagulant therapy.

Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the Levothyroxine Sodium Tablets, USP dose is increased.

Prothrombin time should be closely monitored to permit appropriate and timely dosage adjustments (see Table 2).

Digitalis glycosides – The therapeutic effects of digitalis glycosides may be reduced by levothyroxine.

Serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides (see Table 2).

DRUG INTERACTIONS

Drug Interactions Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs.

If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose.

If a patient receiving clonidine is also taking neuroleptics, orthostatic regulation disturbances (e.g., orthostatic hypotension, dizziness, fatigue) may be induced or exacerbated.

Monitor heart rate in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers, and beta-blockers.

Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concomitantly with diltiazem or verapamil.

Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats (see Toxicology ).

Based on observations in patients in a state of alcoholic delirium it has been suggested that high intravenous doses of clonidine may increase the arrhythmogenic potential (QT-prolongation, ventricular fibrillation) of high intravenous doses of haloperidol.

Causal relationship and relevance for clonidine oral tablets have not been established.