Metolazone

Since metolazone crosses the placenta and appears in cord blood, its administration to women of childbearing age requires that the potential benefits of the drug be weighed against its possible hazards to the fetus. The potential effects on the fetus include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. However, teratogenic studies in mice, rats and rabbits, have not shown teratologic effects in these animals.

Metolazone appears in breast milk. Thus, it is possible that the effects of metolazone may occur in the newborn under these circumstances. If the use of metolazone is deemed essential for a nursing mother, the patient should stop nursing.

Carcinogenicity

Long-term animal studies with metolazone have not shown any evidence of carcinogenicity. Mice and rats given the drug for 18 months to 2 years at doses of 2, 10 and 50 mg/kg by stomach tube, showed no evidence that metolazone caused an increased number of tumors; however, the small number of animals examined histologically, and poor survival in the mice, limit conclusions that can be reached from these studies.

Mutagenicity

A mutagenicity study using Salmonella typhimurium strains TA1535, TA97, TA98, TA100, and TA102 as indicator organisms and concentrations of 100 to 10,000 mcg/plate of metolazone showed no evidence of mutagenic potential.

Reproduction & Teratology

Teratologic studies and studies of reproductive performance in mice, rats and rabbits (including a three-generation study with rats) treated with oral doses ranging from 0.2 to 50 mg/kg showed no evidence of teratologic effects. Reproductive studies in mice and rats have shown no evidence of altered reproductive capacity in mice; however, in a rat study in which males were treated orally with metolazone at doses of 2, 10 and 50 mg/kg for 127 days prior to mating with untreated females, an increased number of resorption sites were observed in dams mated with males from the 50 mg/kg group. In addition, the fetal weight was decreased and the pregnancy rate was reduced in dams mated with males from the 10 and 50 mg/kg group.

The following adverse reactions have been reported. Several are single or comparably rare occurrences. Adverse reactions are listed in decreasing order of severity within body systems.

Cardiovascular: Chest pain/discomfort, orthostatic hypotension, excessive volume depletion, hemoconcentration, venous thrombosis, palpitations.

Central and Peripheral Nervous System: Syncope, neuropathy, vertigo, paresthesias, psychotic depression, impotence, dizziness/lightheadedness, drowsiness, fatigue, weakness, restlessness, sometimes resulting in insomnia), headache.

Dermatologic/Hypersensitivity: Necrotizing angitis (cutaneous vasculitis), Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), purpura, dermatitis (photosensitivity), urticaria and skin rashes.

Gastrointestinal: Hepatitis: intrahepatic cholestatic jaundice, pancreatitis, vomiting, nausea, epigastric distress, diarrhea, constipation, anorexia, abdominal bloating.

Hematologic: Aplastic/hypolastic anemia, agranulocytosis, leukopenia.

Metabolic: Hypokalemia, hyponatremia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hyperglycemia, glycosuria, increase in serum urea nitrogen (BUN) or creatinine, hypophosphatemia.

Musculoskeletal: Joint pain, acute gouty attacks, muscle cramps or spasm.

Other: Transient blurred vision, chills.

In addition, adverse reactions reported with similar antihypertensive diuretics, but which have not been reported to date for metolazone include: bitter taste, dry mouth, sialadenitis, xanthopsia, respiratory distress (including pneumonitis), thrombocytopenia and anaphylactic reactions. These reactions should be considered as possible occurrences with clinical usage of metolazone.

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