Summary Of Exposure |
A) USES: Oral hypoglycemic agents for type II diabetes mellitus.
B) PHARMACOLOGY: These agents decrease hepatic glucose production and intestinal glucose absorption, and increase peripheral glucose uptake.
C) TOXICOLOGY: These agents are not likely to cause hypoglycemia after acute overdose, as they do not stimulate insulin release. Severe lactic acidosis is a rare but potentially fatal side effect mainly in patients with renal insufficiency, hepatic disease, alcoholism, and advanced age. It can be precipitated by iodinated contrast agents. Metformin inhibits both hepatic lactate uptake and conversion of lactate to glucose.
D) EPIDEMIOLOGY: Exposure is common, but severe toxicity is rare.
E) WITH THERAPEUTIC USE
1) COMMON: Diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal pain, anorexia, headache, and rash. SERIOUS EFFECTS: Lactic acidosis (generally only in patients with renal insufficiency or hepatic disease) and megaloblastic anemia. Hypotension, ventricular extrasystoles, and myocardial infarction have been reported with therapeutic doses.
2) DRUG INTERACTION: Use of radiocontrast dyes in patients taking metformin increases the risk of renal failure and acidosis. Concurrent use of metformin and non-steroidal anti-inflammatory drugs or COX-2 inhibitors may increase the risk of renal failure and acidosis.
F) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, malaise, and myalgia. Acute pancreatitis has been reported in one case report.
2) SEVERE TOXICITY: Severe lactic acidosis, confusion, mental status depression, hypothermia, hypotension, and renal failure may develop. Rarely, ventricular dysrhythmias, respiratory insufficiency, and death.
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Vital Signs |
3.3.2) RESPIRATIONS
A) WITH POISONING/EXPOSURE 1) TACHYPNEA has been reported following a metformin overdose (Heaney et al, 1997).
2) KUSSMAUL'S RESPIRATION: Deep, rapid breathing has been reported in patients with biguanide-induced lactic acidosis (Hutchison & Catterall, 1987; Verdonck et al, 1981; Luft et al, 1978).
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) HYPOTHERMIA is common in patients who develop CNS depression associated with buformin or metformin-induced acidosis (Chu et al, 2001; Kruse, 2001; Gan et al, 1992; Chalopin et al, 1984; Ryder, 1984; Verdonck et al, 1981; Luft et al, 1978) .
B) WITH POISONING/EXPOSURE 1) HYPOTHERMIA has been reported in several cases of overdose in which metformin-associated lactic acidosis developed. Core body temperature as low as 27.8 degrees Celsius has been reported (Turkcuer et al, 2009; Yang et al, 2009; von Mach et al, 2004; Chu et al, 2003; Gjedde et al, 2003; Chang et al, 2002).
3.3.4) BLOOD PRESSURE
A) WITH THERAPEUTIC USE 1) HYPOTENSION: Hypotension has been reported with severe metformin and buformin associated acidosis (Ben et al, 2002; Chu et al, 2001; Kruse, 2001; Hutchison & Catterall, 1987; Chalopin et al, 1984; Ryder, 1984; Verdonck et al, 1981; Luft et al, 1978) .
B) WITH POISONING/EXPOSURE 1) Profound hypotension has been reported following metformin overdose in patients with lactic acidosis (Guo et al, 2006; Chang et al, 2002).
3.3.5) PULSE
A) WITH POISONING/EXPOSURE 1) TACHYCARDIA: Pulse rate may be elevated following an overdose (Heaney et al, 1997).
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Heent |
3.4.4) EARS
A) WITH POISONING/EXPOSURE 1) CASE REPORT: Bilateral sensorineural hearing loss developed in a 49-year-old man with type 2 diabetes mellitus 5 days after ingesting 52 grams of metformin and 350 mg of glyburide. Initially, he presented with respiratory distress, lactic acidosis, leukocytosis, and hypotension 6 to 8 hours after the overdose. Despite supportive care, including continuous venovenous hemodialysis, he developed acute renal failure, hyperglycemia, and hypernatremia over the next 12 hours. Following further supportive care, his condition gradually improved and he was extubated on day 5. At this time, audiology test revealed profound sensorineural hearing loss with absent acoustic reflexes about 2 Khz bilaterally. He developed bilateral ear pain with drainage from both ears, tinnitus, and vertigo 8 days after admission. He was treated with prednisone taper and valacyclovir and was diagnosed with malignant otitis externa. A brain MRI revealed a small focal area of evolving ischemia in the left postcentral sulcus region in early subacute stage. His malignant otitis external resolved after therapy with IV and oral ciprofloxacin and ciporofloxacin/dexamethasone ear drops and another otoscopic exam revealed middle ear necrosis and absent tympanic membranes bilaterally. His hearing lost was likely secondary to protracted hypotension and not directly due to the metformin. On follow-up 6 months after the overdose, he continued to have complete bilateral sensorineural hearing loss (Miller et al, 2011).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Hypotension has been reported with severe metformin-induced lactic acidosis (Kumar et al, 2008).
2) WITH POISONING/EXPOSURE a) Hypotension has been reported with severe metformin and buformin associated acidosis (Al-Abri et al, 2013; Miller et al, 2011; Dell'Aglio et al, 2010; Turkcuer et al, 2009; Galea et al, 2007; Guo et al, 2006; Ben et al, 2002; Hutchison & Catterall, 1987; Kruse, 2001; Chalopin et al, 1984; Ryder, 1984; Verdonck et al, 1981; Luft et al, 1978) .
b) CASE SERIES: In a retrospective case series of 36 acute metformin overdoses (doses greater than 3 g; median ingested dose: 10 g; range: 3.5 to 50 g) admitted to a toxicology unit over 20 years, 4 patients developed hypotension, but patients also ingested calcium channel or beta-blockers (n=2), a tricyclic antidepressant (n=1), and an angiotensin II inhibitors (n=1) (McNamara & Isbister, 2015).
c) CASE REPORT: A 44-year-old man with type 2 diabetes mellitus presented with severe abdominal pain and vomiting 3 days after ingesting 35 gliclazide (about 2.1 g) and 35 metformin tablets (about 35 g) in a suicide attempt. He was hypoglycemic (blood sugar concentration of 2.1 mmol/L) on arrival and venous blood gas revealed severe metabolic acidosis, with a pH of 6.88, a bicarbonate level of 4 mmol/L, lactate of 29 mmol/L, a high anion gap of 36 mmol/L, and partial respiratory compensation with a PaCO2 of 23 mmHg. He was transferred to the ICU where his symptoms of encephalopathy worsened, necessitating intubation and ventilation. Laboratory results revealed an acute kidney injury (serum creatinine 326 mcmol/L, urea 9.3 mmol/L). At this time, he underwent hemodialysis (sustained low efficiency daily dialysis [SLEDD] against a high bicarbonate dialysate), but developed severe hemodynamic instability secondary to distributive shock, which was compounded by severe acidemia. Despite treatment with large volume fluid resuscitation, massive doses of vasopressors, stress dose steroids, and empiric antibiotics, his condition did not improve. At this time, treatment with methylene blue (a bolus of 2 mg/kg followed by an infusion at 0.25 mg/kg/hr for about 20 hours) was initiated as a rescue therapy and continued for about 20 hours. His condition gradually improved and he was discharged to the renal ward after a 9-day ICU admission and after 3 sessions of intermittent hemodialysis (Graham et al, 2015).
B) HYPERTENSIVE EPISODE 1) WITH POISONING/EXPOSURE a) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, 6 (2.3%) patients developed hypertension; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), hypertension occurred in 1 patient after ingesting metformin 5000 mg or less and 4 patients after ingesting greater than 5000 mg of metformin(Forrester, 2008).
C) CONDUCTION DISORDER OF THE HEART 1) WITH THERAPEUTIC USE a) Multiple polymorphic ventricular extrasystoles were reported in a 64-year-old woman with severe hypotension and acidosis associated with chronic metformin therapy (Chalopin et al, 1984).
b) CASE REPORT: Cardiac dysrhythmias developed in a 65-year-old woman with metformin-induced hypotension and lactic acidosis. An ECG showed sinus arrest with junctional escape rhythm with an escape rate of 50 to 60 beats/min without ST-T changes. Following supportive therapy, her condition improved gradually and a repeat ECG showed normal sinus rhythm (Kumar et al, 2008).
2) WITH POISONING/EXPOSURE a) Tachycardia has been reported following metformin overdose (Turkcuer et al, 2009; Yang et al, 2009; Guo et al, 2006; Heaney et al, 1997).
b) CASE REPORT: Tachycardia, with a pulse rate of 190/min, was reported following an overdose with an unknown quantity of metformin, glibenclamide, and nabumetone in a previously healthy 29-year-old man (Heaney et al, 1997).
c) Bradycardia and ventricular tachycardia were reported following ingestions of 45 g to 85 g of metformin (Turkcuer et al, 2009; Guo et al, 2006).
d) CASE SERIES: In a retrospective case series of 36 acute metformin overdoses (doses greater than 3 g; median ingested dose: 10 g; range: 3.5 to 50 g) admitted to a toxicology unit over 20 years, 10 patients developed tachycardia. Three patients developed bradycardia, but 2 patients coingested both beta-blockers and calcium channel blockers (McNamara & Isbister, 2015).
D) CARDIAC ARREST 1) WITH THERAPEUTIC USE a) CASE REPORT: A 61-year-old woman with type 2 diabetes and treated with glimepiride 3 mg daily and metformin 850 mg 3 times daily was found with a bradydysrhythmia (55 to 65 bpm and frequent polymorphic ventricular extrasystoles), and was resuscitated successfully after cardiac arrest. Severe metabolic acidosis (pH 6.6 on admission) was also reported on admission, which was attributed to the cardiac events observed (von Mach et al, 2004).
E) MYOCARDIAL INFARCTION 1) WITH THERAPEUTIC USE a) Myocardial infarction may develop in patients with biguanide-induced lactic acidosis. In a series of 330 patients with biguanide induced acidosis, 4 were diagnosed with myocardial infarction at the time lactic acidosis was diagnosed and 13 sustained myocardial infarction during treatment of the acidosis (Luft et al, 1978).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) HYPERVENTILATION 1) WITH THERAPEUTIC USE a) KUSSMAUL'S RESPIRATION: Deep, rapid breathing has been reported in patients with biguanide-induced lactic acidosis (Hutchison & Catterall, 1987; Verdonck et al, 1981; Luft et al, 1978).
B) PNEUMONIA 1) WITH THERAPEUTIC USE a) Leukocytoclastic vasculitis and pneumonitis developed in a 59-year-old woman taking metformin (Klapholz et al, 1986).
C) RESPIRATORY FAILURE 1) WITH THERAPEUTIC USE a) Respiratory failure developed in a 65-year-old woman with metformin-induced lactic acidosis. A chest radiograph showed bilateral infiltrates suggestive of pneumonitis (Kumar et al, 2008).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) CENTRAL NERVOUS SYSTEM DEFICIT 1) WITH THERAPEUTIC USE a) Lethargy and fatigue have been reported (Ilson et al, 1990; Tymms & Leatherdale, 1988; Luft et al, 1978) . Coma is usually associated with hypoglycemia and/or severe acidosis (Heaney et al, 1997; Chalopin et al, 1984; Verdonck et al, 1981) .
2) WITH POISONING/EXPOSURE a) Lethargy and somnolence have been reported with metformin overdose (Turkcuer et al, 2009).
b) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, 8 (3%) patients developed drowsiness/lethargy; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), drowsiness/lethargy occurred in 1 patient after ingesting metformin 5000 mg or less and 4 patients after ingesting greater than 5000 mg of metformin (Forrester, 2008).
c) CASE SERIES: In a retrospective case series of 36 acute metformin overdoses (doses greater than 3 g; median ingested dose: 10 g; range: 3.5 to 50 g) admitted to a toxicology unit over 20 years, GCS of less than 15 and less than 8 were observed in 8 and 2 patients, respectively. All patients also ingested other medications (McNamara & Isbister, 2015).
B) SEIZURE 1) WITH THERAPEUTIC USE a) CASE REPORT: Status epilepticus and coma were reported in a 35-year-old man with alcoholic liver disease and chronic pancreatitis who developed hypoglycemia and lactic acidosis associated with metformin therapy (Ryder, 1984).
b) CASE REPORT/ADOLESCENT: A 14-year-old girl was found following a seizure of unknown duration 4 hours after ingesting metformin, atenolol, and diclofenac (maximum possible ingested doses, metformin 63 g, diclofenac 1050 mg, atenolol 1400 mg). She presented to a local hospital with somnolence (5/15 on the Glasgow Coma Scale) and hypoglycemia (initial blood glucose, 1.9 mmol/L). Despite supportive care, she developed severe lactic acidosis (peak lactate level, 37.5 mmol/L; an albumin corrected anion gap, 65 mmol/L), bradycardia, hypotension, and persistent hypoglycemia. She was successfully treated with high-volume venovenous hemofiltration and aggressive alkalinization therapy with large doses of sodium bicarbonate. She was extubated 78 hours after admission (Harvey et al, 2005).
C) HYPOREFLEXIA 1) WITH POISONING/EXPOSURE a) Abnormal reflexes including loss of corneal reflexes and pupillary response to light, extensor plantar reflexes, and decreased deep tendon reflexes have been reported in patients with coma from biguanide toxicity (Ryder, 1984).
D) PSYCHOMOTOR AGITATION 1) WITH POISONING/EXPOSURE a) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, 5 (1.9%) patients developed agitation/irritability; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), agitation/irritability occurred in 1 patient after greater than 5000 mg of metformin (Forrester, 2008).
E) HEADACHE 1) WITH POISONING/EXPOSURE a) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, 4 (1.5%) patients developed headache; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), headache occurred in 3 patients after ingesting metformin 5000 mg or less and 1 patient after ingesting greater than 5000 mg of metformin (Forrester, 2008).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA 1) WITH THERAPEUTIC USE a) Nausea is a common side effect with therapeutic doses of metformin (Hermann et al, 1994; Giugliano et al, 1993; Josephkutty & Potter, 1990; Menzies et al, 1989) .
b) Nausea may occur in patients with lactic acidosis associated with biguanide therapy (Gan et al, 1992; Hutchison & Catterall, 1987; Luft et al, 1978).
2) WITH POISONING/EXPOSURE a) Severe nausea may occur with overdose (Bebarta et al, 2015; Turkcuer et al, 2009; Ben et al, 2002; Brady & Carter, 1997).
b) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, nausea 16 (6.1%) patients developed nausea; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), nausea occurred in 6 patients after ingesting metformin 5000 mg or less and 4 patients after ingesting greater than 5000 mg of metformin(Forrester, 2008).
c) CASE SERIES: In a retrospective case series of 36 acute metformin overdoses (doses greater than 3 g; median ingested dose: 10 g; range: 3.5 to 50 g) admitted to a toxicology unit over 20 years, 12 (33%) patients developed nausea and/or vomiting (McNamara & Isbister, 2015).
B) VOMITING 1) WITH THERAPEUTIC USE a) Vomiting is a common side effect with therapeutic doses of metformin (Hermann et al, 1994; Giugliano et al, 1993; Josephkutty & Potter, 1990; Menzies et al, 1989) .
b) Vomiting may occur in patients with lactic acidosis associated with biguanide therapy (Gan et al, 1992; Hutchison & Catterall, 1987; Luft et al, 1978).
2) WITH POISONING/EXPOSURE a) Severe vomiting may occur with overdose (Bebarta et al, 2015; Graham et al, 2015; Turkcuer et al, 2009; Ben et al, 2002; Brady & Carter, 1997).
b) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, 21 (8%) patients developed vomiting; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), vomiting occurred in 2 patients after ingesting metformin 5000 mg or less and 9 patients after ingesting greater than 5000 mg of metformin(Forrester, 2008).
c) CASE SERIES: In a retrospective case series of 36 acute metformin overdoses (doses greater than 3 g; median ingested dose: 10 g; range: 3.5 to 50 g) admitted to a toxicology unit over 20 years, 12 (33%) patients developed nausea and/or vomiting (McNamara & Isbister, 2015).
C) DIARRHEA 1) WITH THERAPEUTIC USE a) Diarrhea is common side effect with therapeutic doses of metformin (Hermann et al, 1994; Giugliano et al, 1993; Josephkutty & Potter, 1990; Menzies et al, 1989) .
b) Diarrhea may occur in patients with lactic acidosis associated with biguanide therapy (Gan et al, 1992; Hutchison & Catterall, 1987; Luft et al, 1978).
2) WITH POISONING/EXPOSURE a) Diarrhea may occur with overdose (Bebarta et al, 2015; Turkcuer et al, 2009; Ben et al, 2002; Brady & Carter, 1997).
b) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, 8 (3%) patients developed diarrhea; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), diarrhea occurred in 3 patients after ingesting metformin 5000 mg or less and 1 patient after ingesting greater than 5000 mg of metformin(Forrester, 2008).
D) ABDOMINAL PAIN 1) WITH THERAPEUTIC USE a) Abdominal pain may occur with therapeutic doses of metformin (Hermann et al, 1994; Giugliano et al, 1993; Josephkutty & Potter, 1990; Menzies et al, 1989).
b) Abdominal pain may occur in patients with lactic acidosis associated with biguanide therapy (Gan et al, 1992; Hutchison & Catterall, 1987; Luft et al, 1978).
2) WITH POISONING/EXPOSURE a) Abdominal pain has been reported with metformin overdose (Graham et al, 2015).
b) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, 3 (1.1%) patients developed abdominal pain; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), abdominal pain occurred in 2 patients after greater than 5000 mg of metformin (Forrester, 2008).
E) GASTROINTESTINAL HEMORRHAGE 1) WITH THERAPEUTIC USE a) Gastrointestinal bleeding has been reported in patients with lactic acidosis from chronic therapy (Verdonck et al, 1981).
F) PANCREATITIS 1) WITH POISONING/EXPOSURE a) CASE REPORT: A healthy 21-year-old woman developed acute pancreatitis (a stage B as shown by contrast-enhanced computed tomography; Ranson's criteria of 2 on admission and 0 after 48 hours) after ingesting 53 tablets of 850 mg metformin (45 grams). During the first 24 hours of hospitalization, serum amylase and lipase levels increased to 368 and 1900 UI/L, respectively, and then began to decline. In addition, she developed hypoglycemia (it is not clear if this was primarily due to metformin poisoning, or secondary to acute pancreatitis), hypotension, tachycardia and severe metabolic acidosis (Ben et al, 2002).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) TOXIC HEPATITIS 1) WITH THERAPEUTIC USE a) Babich et al (1998) reported a case of hepatitis associated with therapeutic metformin use in a 52-year-old woman. The patient developed progressive lethargy, diarrhea, and abdominal pain and became icteric several days later. Lab tests were significant for elevated bilirubin of 14.4 mg/dL, AST of 583 International Units/L, ALT of 651 International Units/L, alkaline phosphatase 500 International Units/L, and PT of 13.2 seconds. The patient recovered several weeks after discontinuation of metformin (Babich et al, 1998).
B) INCREASED LIVER ENZYMES 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 24-year-old man presented 2 hours after attempting suicide with metformin (16 g) and telmisartan/hydrochlorothiazide (2.6 g/1.6 g). He was subsequently decontaminated with gastric lavage and activated charcoal. All laboratory results were normal, except for elevated ALT (60 International Units/L). His blood gas analysis revealed a pH of 7.37, pCO2 of 30 mmHg, and HCO3 of 23.7 mmol/L. Lactic acidosis did not occur and his liver enzymes normalized. The patient was subsequently discharged without sequelae (Avci et al, 2013).
b) CASE REPORT: A 29-year-old woman presented to the ED after ingesting 80 g of metformin and a large quantity of ethanol. She threw up most of the pills by vomiting. Gastric lavage and activated charcoal therapy were performed in the internal medicine ICU. Hemodialysis was performed for 6 hours and acidosis did not occur and dialysis was subsequently stopped. Biochemical analysis was normal except for elevated ALT (59 Units/L) and AST (46 International Units/L). On day 5, she was discharged and referred to the gastroenterology department (Avci et al, 2013).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) ACUTE RENAL FAILURE SYNDROME 1) WITH THERAPEUTIC USE a) Acute renal failure may develop in patients with severe biguanide associated lactic acidosis and hypotension (Miller et al, 2011; Chu et al, 2001; Hutchison & Catterall, 1987; Chalopin et al, 1984; Luft et al, 1978) .
b) Renal insufficiency is often a coprecipitating factor in the development of metformin induced acidosis.
c) CASE REPORT: A 73-year-old woman with diabetes, heart disease with atrial fibrillation taking metformin 1000 mg twice daily and warfarin 5 mg daily, developed epistaxis, hematuria, and gingival bleeding with an INR of 16.9 and Hct 27%. Oral vitamin K was given. Renal insufficiency (BUN 53 mg/dL and Cr 3.6 mg/dL) was noted the following day. A CT scan revealed a retroperitoneal hematoma and bilateral perinephric blood clot with obstruction in both renal collecting systems. Approximately 24 hours after admission the patient developed progressive acidosis (pH 7.06; lactate 16.5 mEq/L), and had a cardiopulmonary arrest. The patient was aggressively treated and made a complete recovery. Acute renal insufficiency secondary to obstruction from retroperitoneal bleeding due to a supratherapeutic INR was likely responsible for the metformin induced lactic acidosis in this patient (Schier et al, 2003).
2) WITH POISONING/EXPOSURE a) Acute renal failure may develop in patients with severe metformin associated lactic acidosis (Arroyo et al, 2010).
b) Acute renal failure occurred in 2 patients with severe lactic acidosis and hypotension following intentional ingestion of 45 grams and 50 grams of metformin, respectively. Both patients recovered following prolonged hemodialysis (Guo et al, 2006).
c) CASE REPORT/ADOLESCENT: A 15-year-old girl developed lactic acidosis and reversible acute renal failure (maximum creatinine of 2.4 mg/dL) after ingesting 38.25 g (0.55 g/kg body weight) of metformin in a suicide attempt. Following supportive treatment, including 2 sessions of hemodialysis, she recovered completely and was discharged to the psychiatric ward 2 days later (Lacher et al, 2005).
d) CASE REPORT: A 29-year-old man with no history of diabetes developed acute renal insufficiency, severe lactic acidosis, and rapidly progressive hyperglycemia after ingesting 64 to 85 g of metformin. Despite supportive treatment, he died 25 hours postingestion (Suchard & Grotsky, 2008).
e) CASE REPORT: A 17-year-old nondiabetic girl presented with nausea, vomiting, and diarrhea 15 hours after ingesting 20 of her mother's 500-mg metformin tablets in a suicide attempt. Laboratory results revealed lacticemia and acute kidney injury. She recovered following treatment with only crystalloids. No IV bicarbonate or extracorporeal removal treatments were required (Bebarta et al, 2015).
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Acid-Base |
3.11.2) CLINICAL EFFECTS
A) ACIDOSIS 1) WITH THERAPEUTIC USE a) METFORMIN 1) SUMMARY: Metformin-associated lactic acidosis has been reported in patients taking therapeutic doses of metformin. The clinical definition has been described as a metabolic acidosis (pH < 7.35) along with a blood lactate >5.0 mmol/L in treated patients (Graham et al, 2015; Miller et al, 2011; Yang et al, 2009; Alivanis et al, 2006; Chang et al, 2002; Chu et al, 2001) . However, type 2 diabetics may develop spontaneous lactic acidosis (at about the same rate as acidosis seen in patients on metformin) without metformin therapy (Brown et al, 1998). 2) RISK FACTORS: The condition may be more likely to occur in the presence of impaired renal function or liver or cardiac failure which can lead to hypoxemia or concomitant illness (ie, septicemia, acute hepatic decompensation, alcohol abuse), but cases have occurred when no risk factors have been present (Kumar et al, 2008; Chang et al, 2002; Chu et al, 2001; Kruse, 2001). 3) INCIDENCE: It has been estimated that lactic acidosis has an incidence rate of 0.03 per 1000 patient-years (Chang et al, 2002). a) SURVEILLANCE DATA: Based on data collected from the Toxic Exposure Surveillance System (TESS), 4072 metformin ingestions with known outcome data were reviewed (review period January 1996 through December 2000), and metabolic acidosis was reported in 68 (1.6%) patients over the five-year period (Spiller & Quadrani, 2004).
b) MECHANISM: The pathology for metformin-associated lactic acidosis is complex and not clearly understood. Based on normal function, biguanides accumulate in higher concentrations in the intestines than other tissues, which can double lactate production by the intestine. This can lead to increases in portal lactate levels and decreases in pH of the liver, that can cause a decrease in lactate metabolism due to suppression of pyruvate carboxylase. In addition, high doses of metformin (by overdose or drug accumulation) can decrease glucose utilization and increase lactate production by hepatocytes, and the disease process itself can cause abnormal lactate metabolism. All of these factors may lead to an increase of lactate in the blood (Spiller & Quadrani, 2004).
4) LACK OF EFFECT: Mortality does NOT correlate well with either serum lactate or metformin levels and appears in part to be related to the underlying disease state (eg, sepsis) in some cases (Lalau & Race, 1999). 5) Patients developing lactic acidosis associated with therapeutic use of metformin usually have had underlying renal insufficiency (Schmidt et al, 1997; Wiholm & Myrhed, 1993; Gan et al, 1992; Chalopin et al, 1984; Luft et al, 1978) , liver disease (Wiholm & Myrhed, 1993; Ryder, 1984) , acute renal failure (Jurovich et al, 1997; Lalau et al, 1987; Hutchison & Catterall, 1987) , or other medical problems such as myocardial infarction, congestive heart failure, or sepsis (Wiholm & Myrhed, 1993; Lalau et al, 1987). 6) In a series of 47 patients with confirmed metformin-associated lactic acidosis, 13 (28%) had preexisting renal insufficiency, 30 (64%) had preexisting cardiac disease, 18 (36%) had a history of congestive heart failure, 3 (6%) had chronic pulmonary disease with hypoxia, and 8 (18%) were older than 80 years (Misbin et al, 1998). 7) In a series of 16 patients with metformin-associated acidosis, 14 patients died (Wiholm & Myrhed, 1993). In 9 patients, death was attributed to the acidosis, and in 4 cases the acidosis was felt to have contributed to the patient's demise. 8) CASE REPORT: A 65-year-old diabetic woman with metformin-induced lactic acidosis presented with epigastric pain, vomiting, syncope, bradycardia, hypotension, cardiac dysrhythmias, and respiratory failure. Arterial blood gas analysis revealed a pH 7.12, PO2 97.5 mmHg, PCO2 52.2 mmHg, HCO3 12 mEq/L and an anion gap of 21. The estimated serum lactate level after the resolution of hypotension was 66.80 mg/dL (normal range: 3 to 12). Following supportive therapy, her condition improved gradually over the next 72 hours (Kumar et al, 2008). 9) CASE REPORT: A 75-year-old type 2 diabetic woman receiving metformin 1000 mg twice daily for approximately 1 year was increased to 1000 mg 3 times daily (due to poor glycemic control) 6 days prior to admission, developed lactic acidosis and acute renal failure. Symptoms included acute respiratory distress that required intubation and ventilation, vomiting, diarrhea, hypothermia (32 degrees Celsius), hypotension (67/42 mmHg), and transitory blindness (a rare presentation). A prolonged recovery was reported due to difficulty weaning the patient with a tracheostomy required and the development of pneumonia; however, the patient was discharged 3 months later (Chu et al, 2003). 10) Chu et al (2001) reported that metformin-associated lactic acidosis can present with nonspecific symptoms masquerading as mesenteric ischemia (Chu et al, 2001). 11) CASE REPORT/NO RISK FACTORS: A 40-year-old woman developed lactic acidosis despite therapeutic blood concentrations of metformin and the presence of no risk factors for the development of lactic acidosis. In a review of 47 cases of confirmed metformin-related lactic acidosis cases reported to the FDA, 4 patients had no risk factors (Al-Jebawi et al, 1998). 12) BUFORMIN a) Lactic acidosis has been reported in patients taking therapeutic doses of buformin (Verdonck et al, 1981).
b) Lactic acidosis associated with buformin therapy is much less common than with phenformin therapy. Of 330 cases of biguanide-induced lactic acidosis in one study, 30 were associated with buformin and 281 with phenformin (Luft et al, 1978).
2) WITH POISONING/EXPOSURE a) Lactic acidosis has been reported in patients taking excessive doses of metformin chronically (Lalau et al, 1987), and in patients following overdoses (Al-Abri et al, 2013; Al-Makadma & Riad, 2010; Arroyo et al, 2010; Dell'Aglio et al, 2010; Turkcuer et al, 2009; Suchard & Grotsky, 2008; Galea et al, 2007; Ben et al, 2002; Heaney et al, 1997). b) Severe lactic acidosis (pH less than 7.10; range pH 6.796 to 7.10) along with a blood lactate level of greater than 5.0 mmol/L have been reported following metformin overdose (Guo et al, 2006; Gjedde et al, 2003; Nisse et al, 2003; Chang et al, 2002). c) TIME TO METFORMIN-ASSOCIATED LACTIC ACIDOSIS (MALA): In a retrospective review of regional poison center data for a 13-year period, 42 of 70 patients with metformin overdose (including 40 acute on chronic exposures) developed MALA (defined by a pH less than 7.3 or lactate greater than 5). An additional anti-diabetic medication was used by one-fifth of the patients. MALA was diagnosed within 6 hours in 11 patients, between 6 to 12 hours in 8 patients, and after 12 hours in 7 patients. No time was reported in 14 cases. In 3 of the 4 reported deaths, MALA was diagnosed after the recommended 6 hours of observation period (10 to 24 hours). Overall, 15 of the 26 patients developed MALA after the recommended observation period (Theobald et al, 2015). The metformin formulation (immediate-release vs. extended-release) was not discussed during the study. d) PROGNOSIS: The severity of lactic acidosis correlates with mortality after metformin overdose. A systematic literature review (6 case reports, 1 abstract, 3 case series) determined that metformin overdose patients (n=22) with a nadir serum pH greater than 6.9, a peak serum lactate concentration less than 25 mmol/L, or a peak serum metformin concentration less than 50 mcg/mL were more likely to survive (Dell'Aglio et al, 2009). 1) Overall, 5 of the 22 metformin overdose patients died. Patients with either a serum pH nadir less than or equal to 6.9 or a peak serum lactate concentration of greater than 25 mmol/L had a mortality rate of 83%. Patients with a peak serum metformin concentration of greater than 50 mcg/mL had a mortality rate of 38%. Survivors (n=17) had a median serum pH of 7.3 (interquartile range (IQR) 7.22, 7.36), a median serum lactate concentration of 10.8 mmol/L (IQR 4.2, 12.9), and a median serum metformin concentration of 42 mcg/mL (IQR 6.6, 67.6). Nonsurvivors (n=5) had a median serum pH of 6.71 (IQR 6.71, 6.73), a median serum lactate concentration of 35 mmol/L (IQR 33.3, 39), and a median serum metformin concentration of 110 mcg/mL (IQR 110, 110) (Dell'Aglio et al, 2009).
e) CASE SERIES: In a retrospective case series of 36 acute metformin overdoses (doses greater than 3 g; median ingested dose: 10 g; range: 3.5 to 50 g) admitted to a toxicology unit over 20 years, acid/base status results were available in 25 cases. Coingestants were reported in 23 of these 25 cases and 34 of all 36 cases. Laboratory results revealed a median pH of 7.35 (range, 7.16 to 7.43) and median lactate of 3.9 mmol/L (range, 1.2 to 17 mmol/L) during admission. Ten of the 25 cases developed hyperlactatemia (lactate greater than 2 mmol/L) without acidosis and 11 of the 25 developed hyperlactatemia with acidosis; 5 of these cases had lactic acidosis. A statistical association between dose and lactate and dose and pH was observed. Ten cases with peak lactate of greater than 2 mmol/L had a median time to peak lactate of 6 hours (range, 2 to 19 hours). Although 6 patients were admitted to the ICU with one case of lactic acidosis, no deaths were observed (McNamara & Isbister, 2015). f) In a retrospective chart review of data from 2 regional poison control centers, 132 cases of metformin only overdoses (median dose 15 g; range 9 g to 35 g) were identified. Twelve (9.1%) of these patients developed lactic acidosis (Wills et al, 2010). g) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, 9 (3.4%) patients developed acidosis; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), acidosis occurred in 5 patients after ingesting greater than 5000 mg of metformin (Forrester, 2008). h) Although several clinical conditions (ie., renal or liver failure, hypoxia, concomitant illness like septicemia, alcohol abuse, acute myocardial infarction, cardiovascular collapse, old age, use of radiological contrast media, surgery, pregnancy) have been identified as possible risk factors in developing metformin-induced lactic acidosis, symptoms have developed in the absence of any risk factors in several patients following overdose (Kumar et al, 2008; Horowitz & Rolf, 2002; Chang et al, 2002). 1) CASE REPORT: Six patients with acute renal insufficiency experienced severe acute metabolic acidosis (pH less than 6.9 and bicarbonate less than 5 mEq/L) and increased anion gap after metformin overdose (OrtegaCarnicer et al, 2007).
2) CASE REPORT/ADOLESCENT: A 15-year-old girl presented with somnolence (9/15 on the Glasgow Coma Scale) and metabolic acidosis (pH of 7.29, serum bicarbonate of 17 mmol/L and a base excess of -10 mmol/L) after ingesting 38.25 g (0.55 g/kg body weight) of metformin in a suicide attempt. Her blood glucose and serum lactate concentrations were 166 mg/dL and 6.4 mmol/L, respectively. Approximately 3 hours later, laboratory results showed a worsening metabolic acidosis (pH 7.2, serum bicarbonate of 15 mmol/L, a base excess of -12 mmol/L), blood glucose of 49 mg/dL, serum lactate of 8.7 mmol/L, serum metformin of 165 mg/L, and serum creatinine of 1.48 mg/dL. An initial hemodialysis approximately 5 to 6 hours after ingestion improved the acidosis; however, the serum lactate level rose from 8.7 to 16.3 mmol/L. A further increase in serum lactate 20.6 mmol/L (with a pH of 7.33, serum bicarbonate of 20 mmol/L and a base excess of -5 mmol/L) was observed 5 hours after the end of the first session of hemodialysis. She underwent a second hemodialysis for 5 hours, which lowered the serum lactate to 4.4 mmol/L (Lacher et al, 2005).
3) CASE REPORT/ADOLESCENT: A 14-year-old girl was found following a seizure of unknown duration 4 hours after ingesting metformin, atenolol, and diclofenac (maximum possible ingested doses, metformin 63 g, diclofenac 1050 mg, atenolol 1400 mg). She presented to a local hospital with somnolence (5/15 on the Glasgow Coma Scale) and hypoglycemia (initial blood glucose, 1.9 mmol/L). Despite supportive care, she developed severe lactic acidosis (peak lactate level, 37.5 mmol/L; an albumin corrected anion gap, 65 mmol/L), bradycardia, hypotension, and persistent hypoglycemia. She was successfully treated with high-volume venovenous hemofiltration and aggressive alkalinization therapy with large doses of sodium bicarbonate. She was extubated 78 hours after admission (Harvey et al, 2005).
4) CASE REPORT: A 25-year-old healthy woman took a large, undocumented dose of metformin 5 hours prior to hospital admission. Initial symptoms included nausea, vomiting, and dyspnea. Blood lactate was 33.0 mmol/L and the arterial blood gas (pH 7.10, pCO2 14.4 mmHg, pO2 134.2 mmHg, HCO3 4.4.mmol/L, anion gap 22.6, base deficit 23 mmol/L) indicated severe, increased anion gap acidosis. Within 3 hours, the patient became agitated and developed profound hypotension (BP 49/19 mmHg). Despite supportive care and continuous venovenous hemodiafiltration the patient died of multiple organ failure 2 days after admission (Chang et al, 2002).
5) CASE REPORT: A 58-year-old woman with type II diabetes took a mixed ingestion (20 glibenclamide 5 mg tablets, 62 acarbose 50 mg tablets and 110 metformin 500 mg tablets), and was admitted to the hospital 24 hours later with hypothermia and severe increased anion gap acidosis (pH 6.796, pCO2 12 mmHG, pO2 98.5 mmHg, anion gap 38.2). Blood lactate level was 5.46 mmol/L. Shortly after admission, profound hypotension (BP 54/34 mmHg) developed. Inotropic agents were started, and intubation was performed. In addition, the patient received 2.5 hours of bicarbonate hemodialysis, which gradually improved her arterial blood pH and stabilized her blood pressure even without inotropic agents. The patient was discharged to home within 3 days (Chang et al, 2002).
i) METABOLIC ACIDOSIS: A healthy 21-year-old woman developed acute pancreatitis after ingesting 53 tablets of 850 mg metformin (45 grams). In addition, she developed hypoglycemia (it is unclear if the initial hypoglycemia was primarily due to metformin poisoning, or secondary to acute pancreatitis), hypotension, tachycardia, and severe metabolic acidosis (pH 6.96, PaO2 136 mmHg, PaCO2 15 mmHg, HCO3 3.4 mmol/L, SaO2 97% with an ion gap of 37 mEg/L) (Ben et al, 2002). j) CASE REPORT: Suicide attempt by overdose with an unknown quantity of metformin, glibenclamide, and nabumetone was reported in a previously healthy 29-year-old man. Profound lactic acidosis occurred, with a serum lactate level of 31 mmol/L. The patient recovered following hemodialysis for 10 hours with a sodium bicarbonate buffer (Heaney et al, 1997). k) FATALITIES: Severe lactic acidosis from metformin overdose resulted in death of 2 patients with type 2 diabetes (Palatnick et al, 1999). l) CASE REPORT: Close correlations between plasma metformin and creatinine clearance have been seen in patients with normal renal function, as well as in patients with moderate or severe renal failure. However, a 65-year-old man with massive metformin accumulation developed lactic acidosis despite a mild increase in serum creatinine (Lalau et al, 1998b). m) CASE SERIES: In a series of 13 patients with metformin overdose, 11 patients had elevated lactate levels, with lactic acidosis developing in 7 patients (Lalau et al, 1998a). n) PEDIATRIC: In a series of 46 cases of metformin ingestion (dose ranged from 250 mg to 16.5 g) in children, no patient experienced hypoglycemia or lactic acidosis (Spiller et al, 1999). o) CASE REPORT: A 17-year-old woman, with a history of major depression, presented lethargic 4 hours after ingesting 75 metformin pills (1000 mg each) and 20 rupatadine pills (a second-generation antihistamine, 10 mg each) in a suicide attempt. Gastric lavage and activated charcoal therapy were performed immediately. Laboratory results revealed a blood glucose of 12 mg/dL and she was started on 20% dextrose infusion immediately. Her arterial blood gas analysis revealed acidosis (pH: 7.216, pCO2: 27 mmHg, base excess: -15.5, HCO3: 10.7 mmol/L); her initial lactate level was 48 mg/dL and her blood pH declined shortly after to 7.008. Continuous HCO3 infusion and hemodialysis were started but despite 4 hours of hemodialysis, her blood pH did not normalize. Recurrent hemodialysis was performed but the patient developed sudden ventricular tachycardia during the second hemodialysis. She did not respond to cardiopulmonary resuscitation efforts and died (Avci et al, 2013). p) CASE REPORT: A 20-year-old man presented to the ED with nausea and vomiting 6 hours after ingesting many pills of diclofenac sodium and 28 g of metformin. He was transferred to the internal medicine ICU after gastric lavage and activated charcoal therapy were performed. His initial blood gas analysis revealed acidosis (pH: 7.314; pCO2: 42.2 mmHg; HCO3: 20.9 mmol/L, and base excess: -5.5 mmol/L). After 7 hours of hemodialysis, his arterial blood gases were normalized and acidosis did not occur again. He was transferred to the psychiatric clinic after he recovered on day 5 (Avci et al, 2013). q) CASE REPORT: A 17-year-old nondiabetic girl presented with nausea, vomiting, and diarrhea 15 hours after ingesting 20 of her mother's 500-mg metformin tablets in a suicide attempt. Laboratory results revealed lacticemia and acute kidney injury. She recovered following treatment with only crystalloids. No IV bicarbonate or extracorporeal removal treatments were required (Bebarta et al, 2015). |
Hematologic |
3.13.2) CLINICAL EFFECTS
A) HEMOLYSIS 1) WITH THERAPEUTIC USE a) A 46-year-old man developed hemolysis, jaundice, and fatigue 10 days after taking metformin 500 mg 3 times daily. Laboratory analysis was significant for elevated total bilirubin peaking at 6.6 mg/dL that coincided with a hematocrit of 37.6%. After discontinuation of metformin, hemolysis, jaundice, and hyperbilirubinemia resolved (Lin et al, 1998). Hemolysis recurred with rechallenge.
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) VASCULITIS 1) WITH THERAPEUTIC USE a) CASE REPORT: Leukocytoclastic vasculitis manifested by purpuric papules on the lower abdomen, thighs, forearms and buttocks, and pneumonitis developed in a 59-year-old woman taking metformin (Klapholz et al, 1986). The eruption resolved with steroid therapy and recurred when metformin was reintroduced.
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) RHABDOMYOLYSIS 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 46-year-old man presented with vomiting, diarrhea, abdominal pain, and tachypnea after ingesting 56 g of metformin, 35 mg of ramipril, and 500 mL of ethanol. Laboratory results revealed marked metabolic acidosis with a high lactate level, and abnormal renal function. After becoming hypotensive and apneic in the ICU, he experienced an asystolic cardiac arrest requiring 4 cycles of cardiopulmonary resuscitation. High-volume continuous venovenous hemofiltration (CVVHF) (3.5 L/hr or 50 mL/kg/hr; blood flow 250 mL/min) was started 15 hours post-ingestions, but no improvement of severe lactic acidosis was observed after 6 hours. At this time, high-volume CVVHF (blood flow 300 mL/min with a filtrate flow rate of 5 L/hr [72 mL/kg/hr]) was started. Lactic acidosis improved after 16 hours of hemofiltration and he became hemodynamically stable. A diagnosis of compartment syndrome and rhabdomyolysis (CK peaked at 12478 International Units/L) was made on day 2 after he complained of severe left lower limb pain. On day 5, despite supportive care and a fasciotomy, an above knee amputation was required. Although a causal link between metformin or ramipril and rhabdomyolysis was not reported, it was suggested that rhabdomyolysis may have been caused by hypotension, hypothermia, lactic acidosis, cardiac arrest, inotrope infusions, diabetes myonecrosis, or focal seizures. His condition gradually improved and he was discharged home with normal renal function (Galea et al, 2007).
|
Endocrine |
3.16.2) CLINICAL EFFECTS
A) HYPOGLYCEMIA 1) WITH THERAPEUTIC USE a) Hypoglycemia may also develop in patients with biguanide-associated lactic acidosis, but it is rare after acute overdose (Harvey et al, 2005; Kruse, 2001; Tymms & Leatherdale, 1988; Ryder, 1984; Luft et al, 1978) . 1) CASE SERIES: In a series of 46 cases of metformin ingestion (dose ranged from 250 mg to 16.5 g) in children, no patient experienced hypoglycemia or lactic acidosis (Spiller et al, 1999).
2) WITH POISONING/EXPOSURE a) Hypoglycemia has been reported following metformin overdose, but is not common (Graham et al, 2015; Al-Abri et al, 2013; Yang et al, 2009; Guo et al, 2006; Spiller & Quadrani, 2004; Ben et al, 2002).
b) SURVEILLANCE DATA: Based on data collected from the Toxic Exposure Surveillance System (TESS), 4072 metformin ingestions with known outcome data were reviewed (review period January 1996 through December 2000), and hypoglycemia was reported in 112 (2.8%) cases. This rate is higher than previously reported in other studies (Spiller & Quadrani, 2004).
c) CASE SERIES: In a retrospective case series of 36 acute metformin overdoses (doses greater than 3 g; median ingested dose: 10 g; range: 3.5 to 50 g) admitted to a toxicology unit over 20 years, 8 patients developed hypoglycemia (McNamara & Isbister, 2015).
d) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, 4 (1.5%) patients developed hypoglycemia; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), hypoglycemia occurred in 1 patient after ingesting metformin 5000 mg or less and 2 patients after ingesting greater than 5000 mg of metformin (Forrester, 2008).
e) CASE REPORT: Severe hypoglycemia has been reported in one patient after an acute overdose; this patient also had pancreatitis (Ben et al, 2002).
f) Hypoglycemia occurred in 2 patients with severe lactic acidosis following intentional ingestion of 45 and 50 grams of metformin, respectively. Both patients recovered following prolonged hemodialysis (Guo et al, 2006).
g) CASE REPORT: A 15-year-old girl presented 2 hours after ingesting 150 tablets or metformin (500 mg) and 30 tablets of quetiapine (100 mg). She developed lethargy and metabolic acidosis. Two hours after ED presentation fingerstick blood glucose was 15 mg/dL (confirmed on a second sample) and she was drowsy. She was treated with 50 mL 50% dextrose with improvement in her mental status and blood glucose, and an infusion of 5% dextrose was started. Dextrose infusion was interrupted 9 hours after presentation and her blood glucose dropped to 20 mg/dL. She received 50 g of IV dextrose and was started on an infusion of 10% dextrose. She developed severe lactic acidosis, was treated with hemodialysis but had no further episodes of hypoglycemia. Serum was analyzed for acetohexamide, carbutamide, chlorpropamide, tolbutamide, tolazamide, glipizide, gliclazide, glyburide, glibornuride, gliquidone, glisoxepide, glyclopyramide, and glimepiride using a high-resolution mass spectrometer and no sulfonylurea was detected. The patient recovered without sequelae (Al-Abri et al, 2013).
B) HYPERGLYCEMIA 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 29-year-old man with no history of diabetes developed acute renal insufficiency, severe lactic acidosis, and rapidly progressive hyperglycemia (glucose, 707 mg/dL 30 minutes after presentation) after ingesting 64 to 85 g of metformin. Despite supportive treatment, he died 25 hours postingestion (Suchard & Grotsky, 2008).
b) CASE SERIES: In a retrospective review of 264 adult metformin ingestions collected by the Texas Poison Center Network during 2000 to 2006, 11 (4.2%) patients developed hyperglycemia; of the 175 (66.3%) cases where the dose ingested was known (mean dose: 4739 mg; range, 500 to 60,000 mg), hyperglycemia occurred in 4 patients after ingesting metformin 5000 mg or less and 2 patients after ingesting greater than 5000 mg of metformin(Forrester, 2008).
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Reproductive |
3.20.1) SUMMARY
A) Metformin is classified as FDA pregnancy category B. The combinations of metformin hydrochloride/saxagliptin hydrochloride, sitagliptin/metformin hydrochloride, and alogliptin benzoate/metformin hydrochloride are classified as FDA pregnancy category B. The combinations of dapagliflozin propanediol/metformin hydrochloride, empagliflozin/metformin, and pioglitazone hydrochloride/metformin hydrochloride are classified as FDA pregnancy category C. Although metformin reduced the rate of first-trimester spontaneous abortion in 19 pregnant women with polycystic ovary syndrome, it did not appear to be teratogenic. In animal reproduction studies conducted by the manufacturer, metformin was not teratogenic in rats and rabbits.
3.20.2) TERATOGENICITY
A) LACK OF EFFECT 1) METFORMIN a) The rate of major birth defects was not significantly different after metformin treatment during the first trimester in pregnant women with polycystic ovarian syndrome (PCOS) compared with a disease-matched control group in a meta-analysis of 9 controlled, retrospective, or prospective studies. There was also no significant heterogeneity among the studies (p=0.71). There were 3 major birth defects in the metformin-exposed group (n=351) versus 2 in the control group (n=178) (odds ratio, 0.86; 95% CI, 0.18 to 4.08). In evaluating data from 16 non-overlapping studies in PCOS that were excluded from the meta-analysis due to the inclusion of an inappropriate control group, the overall rate of major anomalies was 0.6% in the group of women who discontinued therapy upon conception or confirmation of pregnancy (n=517) and 0.5% in the group of women who were treated with metformin throughout the first trimester of pregnancy (n=634). The number of studies of first-trimester metformin exposure in pregnant women with type 2 diabetes that met the inclusion criteria was insufficient to draw firm conclusions or perform a meta-analysis (Cassina et al, 2014).
B) ANIMAL STUDIES 1) METFORMIN a) In an in vitro study of mouse embryogenesis, metformin was found to delay closure of the neural pores but did not alter embryonic growth and was not associated with malformations (Denno & Sadler, 1994).
b) Metformin was not teratogenic in rats and rabbits at doses up to 6 times the maximum recommended human daily dose of 2000 mg based on body surface area (Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010; Prod Info XIGDUO(TM) XR oral extended release tablets, 2014).
2) COMBINATION PRODUCTS a) CANAGLIFLOZIN/METFORMIN 1) Coadministration of canagliflozin and metformin to pregnant rats during organogenesis did not result in any adverse developmental rats at doses up to 11 and 13 times, respectively, the clinical doses of canagliflozin and metformin (Prod Info INVOKAMET(R) oral tablets, 2016).
b) METFORMIN/ALOGLIPTIN 1) There was no evidence of fetal abnormalities after the administration to pregnant rats of approximately 28 times the clinical dose of 25 mg alogliptin and 2 times the clinical dose of 2000 mg metformin based on AUC (Prod Info KAZANO oral tablets, 2013)
c) METFORMIN/EMPAGLIFLOZIN 1) The coadministration of empagliflozin and metformin in pregnant animals did not result in teratogenicity at exposures up to 35 times the clinical exposure based on AUC (Prod Info SYNJARDY(R) oral tablets, 2015).
d) METFORMIN/LINAGLIPTIN 1) The coadministration of linagliptin and metformin at doses similar to the maximum recommended clinical dose to pregnant animals during organogenesis resulted in no adverse maternal or developmental outcomes. In animal studies with the individual components, linagliptin was not teratogenic in animals administered doses up to 1943 times the clinical human dose during organogenesis. In addition, the administration of linagliptin to pregnant animals during gestation day 6 through lactation day 21 resulted in no toxic effects in offspring exposed to 49 times the maximum recommended human dose. Metformin was not teratogenic in animals administered up to 3 times the clinical human dose. However, an increased incidence of fetal rib and scapula skeletal malformations was observed in animals administered metformin at higher maternally toxic doses (9 and 23 times the clinical exposure at recommended doses) (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016).
e) METFORMIN/SAXAGLIPTIN 1) In animal studies, no embryolethality or teratogenicity was noted in rats and rabbits administered the metformin/saxagliptin combination at doses up to 100 times and 10 times the maximum recommended human doses (MRHD), respectively, in rats and 249 times and 1.1 times the MRHD, respectively, in rabbits. Developmental toxicity included an increased incidence of wavy ribs in rats and fetal body weight losses of 7% and a low incidence of fetal hyoid delayed ossification in rabbits (Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) Metformin is classified as FDA pregnancy category B (Prod Info Glucophage(R), 2001).
2) The combinations of metformin hydrochloride/saxagliptin hydrochloride, sitagliptin/metformin hydrochloride, and alogliptin benzoate/metformin hydrochloride are classified as FDA pregnancy category B (Prod Info JANUMET(R) XR oral extended-release tablets, 2012; Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010; Prod Info KAZANO oral tablets, 2013).
3) The combinations of dapagliflozin propanediol/metformin hydrochloride, empagliflozin/metformin hydrochloride, and pioglitazone hydrochloride/metformin hydrochloride are classified as FDA pregnancy category C (Prod Info SYNJARDY(R) oral tablets, 2015; Prod Info XIGDUO(TM) XR oral extended release tablets, 2014; Prod Info ACTOPLUS MET(R) oral tablets, 2012; Prod Info ACTOPLUS MET(R) XR oral extended-release tablets, 2009).
4) CANAGLIFLOZIN/METFORMIN: Because animal data have shown adverse renal effects, use alternatives to canagliflozin/metformin hydrochloride, particularly during the second and third trimesters of pregnancy. Discuss the potential for unintended pregnancy with premenopausal women because metformin use may result in ovulation in some anovulatory women (Prod Info INVOKAMET(R) oral tablets, 2016)
5) METFORMIN/LINAGLIPTIN: There are no adequate or well-controlled studies of the linagliptin/metformin hydrochloride combination product or its individual components in pregnant women. Although the metformin component has been reported to cross the human placental barrier, some clinical data show that metformin administration during the first trimester was not associated with an increased risk for malformation nor increased perinatal complications. The use of metformin in premenopausal women may result in ovulation and unintended pregnancy in anovulatory women. Advise women that treatment with metformin may result in an unintended pregnancy in some premenopausal anovulatory females (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016). Administer the linagliptin/metformin combination product during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.
B) LACK OF EFFECT 1) METFORMIN a) Although metformin reduced the first-trimester spontaneous abortion rate in 19 pregnant women with polycystic ovary syndrome, it did not appear to be teratogenic (Glueck et al, 2001).
b) Perinatal complications in the neonate did not increase in those exposed in utero to metformin compared with insulin in a randomized open-label trial of 751 women with gestational diabetes. Pregnant women with gestational diabetes and a single fetus between 20 and 33 weeks of gestation were randomized to oral metformin (500 mg once or twice daily and titrated over 1 to 2 weeks to a maximum dose of 2500 mg/day; supplemental insulin as required) or subQ insulin. The composite of neonatal complications (primary outcome) was 32% and 32.2% (relative risk [RR], 0.99; 95% CI, 0.8 to 1.23; p=0.95) for the metformin group and the insulin group, respectively. Neonatal complications included in the composite (with individual rates for metformin and insulin groups reported, respectively) were recurrent blood glucose level less than 46.8 mg/dL (15.2% and 18.6%; RR, 0.81; 95% CI, 0.59 to 1.12); respiratory distress (3.3% and 4.3%; RR, 0.76; 95% CI, 0.37 to 1.59); phototherapy (8% and 8.4%; RR, 0.95; 95% CI, 0.59 to 1.55); birth trauma (4.4% and 4.6%; RR, 0.96; 95% CI, 0.49 to 1.87); 5-minute Apgar score less than 7 (0.8% and 0.3%, respectively; RR, 3.06; 95% CI, 0.32 to 29.26); and preterm birth (less than 37 weeks of gestation) (12.1% and 7.6%; RR, 1.6; 95% CI, 1.02 to 2.52). There were 11 reports of congenital anomalies in the metformin group and 18 in the insulin group (Rowan et al, 2008).
c) No difference was demonstrated in body fat between the offspring who were exposed in utero to metformin and/or insulin in a 2-year follow-up study (n=318). Total fat was 16.4% +/- 4.9% in the metformin-exposed group (adjusted age, 28.7 +/- 3.6 months) and 16.9% +/- 4% (p=0.34) in the insulin-exposed group (adjusted age, 29.4 +/- 3.8 months) per total body dual-energy X-ray absorptiometry measurement and 16.5% +/- 9.07% and 17.1% +/- 6.99%, respectively, (p=0.58) per bioimpedance analysis. Of 11 anthropometry measurements, upper-arm circumferences (17.2 +/- 1.5 cm versus 16.7 +/- 1.5 cm, respectively; p=0.002), subscapular skinfold thickness 6.3 +/- 1.9 mm versus 6 +/- 1.7 mm, respectively; p=0.02), and biceps skinfold thickness (6.03 +/- 1.9 mm versus 5.6 +/- 1.7 mm, respectively; p=0.04) increased in the metformin group's versus insulin group's offspring (Rowan et al, 2011).
C) ANIMAL STUDIES 1) METFORMIN/SAXAGLIPTIN a) Developmental toxicity, including an increased incidence of wavy ribs in rats and fetal body weight losses of 7% and a low incidence of fetal hyoid delayed ossification in rabbits, was reported following the administration of a combination of metformin and saxagliptin at doses up to 100 times and 10 times the maximum recommended human doses (MRHD; saxagliptin 5 mg and metformin 2000 mg), respectively, in rats, and 249 times and 1.1 times the MRHD, respectively, in rabbits. Maternal toxicity included weight loss (11% to 17%) and related reductions in food consumption in rats and marginal reductions in body weight in rabbits. In a subset analysis of rabbits, death, moribundity, or abortion were reported in 12 of 30 mothers (Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) METFORMIN a) Motor and social development, growth, and illness requiring a visit to the pediatrician were studied in 61 breastfed and 50 formula-fed infants born to 92 mothers with polycystic ovary syndrome taking 1.5 to 2.55 g (median, 2.55 g) metformin daily throughout pregnancy and lactation. No sex-based differences were observed for weight, height, or motor and social development at 3 and 6 months between breastfed and formula-fed infants. No infants were identified as having delayed growth, motor, or social development. There was no difference in intercurrent illness requiring a visit to the pediatrician between breastfed and formula-fed infants at 3 months (30% and 22%, respectively) or 6 months (46% and 34%, respectively) (Glueck et al, 2006).
2) COMBINATION PRODUCTS a) CANAGLIFLOZIN/METFORMIN 1) While it is unknown whether the canagliflozin/metformin combination or canagliflozin alone is excreted in human breast milk, limited data from published studies show that metformin is excreted into human milk. Nursing infants whose mothers were receiving metformin were exposed to doses approximately 0.11% to 1% of the maternal weight-adjusted dosage, with a milk/plasma ratio between 0.13 and 1. Canagliflozin is excreted into the milk of lactating rats and juvenile rats directly exposed to canagliflozin had renal pelvic and tubular dilatations during maturation. Because of the potential for serious adverse reactions, including risk to the developing kidney, in the nursing infant, advise lactating women not to use canagliflozin/metformin hydrochloride while breastfeeding (Prod Info INVOKAMET(R) oral tablets, 2016).
b) METFORMIN/ALOGLIPTIN 1) At the time of this review, no data were available to assess the potential effects of exposure to linagliptin/metformin during lactation in humans. It is unknown whether linagliptin is excreted into human milk or has adverse effects on milk production or the breastfed infant. However, it has been shown to be excreted into rat milk. Limited data suggest that metformin is excreted into human milk, but there is insufficient information about whether it adversely effects milk production or the breastfed infant. Consider the mother's need for linagliptin/metformin hydrochloride against the developmental and health benefits of breastfeeding and the potential adverse effects of its exposure in the breastfed infant (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016).
c) METFORMIN/EMPAGLIFLOZIN 1) Metformin is known to be secreted into human milk; however, no effects on breastfed infants have been reported. Empagliflozin is excreted into the milk of lactating animals at a dose 5 times higher than that of maternal plasma; however, because kidney development occurs in utero and during the first 2 years of life, there is an increased risk of harm to a developing human kidney. The empagliflozin/metformin hydrochloride combination should not be used by nursing mothers (Prod Info SYNJARDY(R) oral tablets, 2015).
d) METFORMIN/SAXAGLIPTIN 1) Lactation studies of the metformin hydrochloride and saxagliptin hydrochloride combination have not been conducted in humans; therefore, it is unknown whether saxagliptin is excreted into human milk. Animal studies of the individual components of metformin hydrochloride and saxagliptin hydrochloride showed that both metformin and saxagliptin are excreted into the milk of lactating rats (Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010).
3.20.5) FERTILITY
A) UNINTENDED PREGNANCY 1) The use of metformin in premenopausal women may result in ovulation and unintended pregnancy in anovulatory women (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016).
B) LACK OF EFFECT 1) METFORMIN a) No evidence of impaired fertility was noted after the administration of metformin to male and female rats at doses approximately 2 times the maximum recommended human dose based on body surface area (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016).
2) METFORMIN/DAPAGLIFLOZIN a) There was no evidence of fertility impairment in male and female rats administered doses of dapagliflozin/metformin hydrochloride up to approximately 3 times the maximum recommended human dose (Prod Info XIGDUO(TM) XR oral extended release tablets, 2014).
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