Metoprolol tartrate and hydrochlorothiazide

Catecholamine-depleting drugs (e.g., MAO inhibitors): Hypotension, bradycardia. ( 7.1 ) CYP2D6 inhibitors: Increased metoprolol concentration. ( 12.3 ) Digitalis glycosides, clonidine, diltiazem and verapamil: Bradycardia. ( 5.4 , 7.1 ) Clonidine: Rebound hypertension following clonidine withdrawal. ( 7.1 ) Antidiabetic drugs: Dosage adjustment may be required. ( 7.2 ) Cholestyramine and colestipol: Reduced absorption of thiazides. ( 7.2 ) Lithium: Risk of lithium toxicity. ( 7.2 ) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Reduced diuretic, natriuretic, and antihypertensive effects of diuretics. ( 7.2 )

7.1 Drug Interactions with Metoprolol Catecholamine Depleting Drugs: The concomitant use of catecholamine-depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) with beta adrenergic blockers may have an additive affect and increase the risk of hypotension or bradycardia CYP2D6 Inhibitors: Drugs that are strong inhibitors of CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone were shown to double metoprolol concentrations. While there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. Increases in plasma concentration decrease the cardioselectivity of metoprolol [see Clinical Pharmacology ( 12.3 )] .

Monitor patients closely when the combination cannot be avoided. 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.

7.2 Drug Interactions with Hydrochlorothiazide Antidiabetic drugs (oral agents and insulin) : Dosage adjustment of the antidiabetic drug may be required. Ion exchange resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Stagger the dosage of hydrochlorothiazide and ion exchange resins ( e.g., cholestyramine and colestipol resins ) such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins to minimize the interaction. Lithium : Diuretics reduce the renal clearance of lithium and increase the risk of lithium toxicity. Monitor serum lithium concentrations during concurrent use. Non-Steroidal Anti-Inflammatory Drugs : NSAIDs can reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics.

8.1 Pregnancy Risk Summary Untreated hypertension during pregnancy can lead to adverse outcomes for the mother and the fetus ( see Clinical Considerations ). Available data from published observational studies have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with metoprolol use during pregnancy. However, there are inconsistent reports of intrauterine growth restriction, preterm birth, and perinatal mortality with maternal use of beta blockers, including metoprolol, during pregnancy ( see Data ).

There have been rare reports of jaundice, thrombocytopenia, and electrolyte imbalances in infants exposed to thiazide medications during pregnancy. In animal reproduction studies, metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages up to 24 times, on a mg/m 2 basis, the daily dose of 200 mg in a 60-kg patient. The combination of metoprolol tartrate/hydrochlorothiazide administered to rats from mid-late gestation through lactation also produced increased post-implantation loss and decreased neonatal survival ( see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical consideration Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).

Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal adverse reactions Metoprolol Metoprolol crosses the placenta. Neonates born to mothers who are receiving metoprolol during pregnancy, may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Observe neonates for symptoms of hypotension, bradycardia, hypoglycemia and respiratory depression and manage accordingly.

Data Human Data Data from published observational studies did not demonstrate an association of major congenital malformations and use of either metoprolol or hydrochlorothiazide in pregnancy. The published literature has reported…