GLIPIZIDE-METFORMIN (glipizide/metformin hcl)

There are 8 contraindications. Absolute contraindication.

Contraindication List
Alcohol intoxication
Alcohol use disorder
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Chronic kidney disease stage 5 (failure) GFr<15 ml/min
Dehydration
Metabolic acidosis
Sepsis
Shock

There are 12 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acute decompensated heart failure
Acute myocardial infarction
Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
Debilitation
Disease of liver
Hepatic porphyria
High fever >101 degrees fahrenheit
Hypoglycemic disorder
Kidney disease with likely reduction in glomerular filtration rate (GFr)
Severe diarrhea
Severe hypoxemia
Severe vomiting

There are 12 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Alcohol use disorder
Debilitation
Disease of liver
Fever
Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
Hemolytic anemia
Hypothyroidism
Infection
Kidney disease with reduction in glomerular filtration rate (GFr)
Pituitary insufficiency
Primary adrenocortical insufficiency
Vitamin b12 deficiency

There are 29 severe adverse reactions.

More Frequent	Less Frequent
Hypoglycemic disorder	Dyspnea

Rare/Very Rare

Abnormal hepatic function tests Acute respiratory distress syndrome Agranulocytosis Aplastic anemia Autoimmune hemolytic anemia Autoimmune hepatitis Blood dyscrasias Cholestasis Cholestatic hepatitis Gastrointestinal hemorrhage Hemolytic anemia Hepatic failure Hepatic porphyria Hepatitis Hepatocellular damage Hypoglycemic disorder Hyponatremia Lactic acidosis Leukopenia Maculopapular rash Megaloblastic anemia Obstructive hyperbilirubinemia Pancreatitis Pancytopenia Porphyria cutanea tarda SIADH syndrome Thrombocytopenic disorder

There are 39 less severe adverse reactions.

More Frequent	Less Frequent
Abdominal distension Constipation Diarrhea Dizziness Drowsy Dysgeusia Flatulence Headache disorder Nausea Nervousness Tremor Upper respiratory infection Vitamin b12 deficiency Vomiting Weight loss	Acute abdominal pain Chills Constipation Dizziness Dyspepsia Flu-like symptoms Flushing General weakness Hyperhidrosis Myalgia Nail disorders Palpitations Rhinitis Weight gain

Rare/Very Rare
Acute abdominal pain Anticholinergic toxicity Drowsy Eczema Erythema Gastrointestinal irritation Pruritus of skin Skin photosensitivity Skin rash Urticaria

The manufacturer states that available data from a small number of published studies and postmarketing experience with use of extended-release glipizide in pregnancy over decades have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal outcomes. Glipizide has been shown to be mildly fetotoxic in rats when given at doses of 5-50 mg/kg; the fetotoxic effect is perinatal and similar to that of some other sulfonylureas, and is believed to be directly related to the hypoglycemic effect of the drug. There were no effects on embryofetal development following administration of glipizide to pregnant rats and rabbits during organogenesis at doses 833 and 8 times, respectively, the human dose based on body surface area.

No teratogenic effects were observed in reproduction studies in rats or rabbits. However, increased pup mortality was observed in rats given glipizide from gestation day 15 throughout lactation at dosages twice the maximum human dose based on body surface area. Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, miscarriage, preterm delivery, stillbirth, and delivery complications.

In addition, poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Many experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration. Use of glipizide in pregnant women is generally not recommended, and the drug should be used during pregnancy only when clearly necessary (e.g., when insulin therapy is infeasible).

Neonates born to women with gestational diabetes that was treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may develop respiratory distress, hypoglycemia, or birth injury; they also may be large for gestational age. Sulfonylureas, including glipizide, cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Prolonged, severe hypoglycemia lasting 4-10 days has been reported in some neonates born to women who were receiving sulfonylurea antidiabetic agents up to the time of delivery; this effect has been reported more frequently with the use of those agents having prolonged elimination half-lives.

To minimize the risk of neonatal hypoglycemia if glipizide is used during pregnancy, the manufacturer recommends that the drug be discontinued at least 2-4 weeks before the expected delivery date. Neonates should be observed for symptoms of hypoglycemia and respiratory distress and managed accordingly. Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum recommended human daily dosage based on body surface area or about 3 and 6 times the maximum recommended human daily dosage of extended-release tablets (2 g) based on body surface area comparisons with rats and rabbits, respectively) have not revealed evidence of harm (e.g., teratogenicity) to the fetus.

Determination of fetal concentrations of metformin suggest that a partial placental barrier to the drug exists. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, most experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes mellitus who have an HbA1c exceeding 7 and has been reported to be as high as 20-25% in women with a HbA1c exceeding 10.

The estimated background risk of miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Available studies on the use of metformin in pregnant women have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Limited data from uncontrolled or retrospective studies are conflicting with regard to the effects of long-term maternal therapy with metformin hydrochloride (1.5-3 g daily) on neonatal morbidity (e.g., congenital malformations) and mortality. Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Metformin should be used during pregnancy only when clearly needed.

Although it is not known whether glipizide is distributed into milk in humans, some sulfonylurea antidiabetic agents are distributed into milk. Because of the potential for hypoglycemia in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. If glipizide is used during breast-feeding, infants should be monitored for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

If glipizide is discontinued, and if dietary management alone is inadequate for controlling blood glucose concentration, administration of insulin should be considered. Metformin is distributed into milk in lactating rats. Limited data indicate that small amounts of metformin also are distributed into breast milk in humans.

In a study in 7 nursing women who received metformin hydrochloride (median dosage 1500 mg daily), the mean milk-to-plasma ratio for metformin was 0.35 and the overall average concentration in milk over the dosing interval was 0.27 mg/L.

Metformin was present in low or undetectable amounts in the plasma of 4 breast-fed infants, and no adverse effects were noted in 6 infants that were evaluated. In another study, mean peak and trough metformin concentrations in 4 nursing women receiving metformin hydrochloride 500 mg twice daily were 1.06 and 0.42

mcg/mL, respectively, in serum and 0.42 and 0.39 mcg/mL, respectively, in breast milk.

The mean milk-to-serum ratio was 0.63 and the mean estimated infant dose as a percentage of the mother's weight-adjusted dose was 0.65%.

Blood glucose concentrations obtained in 3 infants 4 hours after breastfeeding were within normal limits (47-77 mg/dL). The developmental and health benefits of breastfeeding should be considered along with mother's clinical need for the drug and potential adverse effects on the breastfed child (e.g., hypoglycemia). Breastfed infants should be monitored for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

No enhanced Geriatric Use information available for this drug.