Topiramate Capsules

Dosage Form: sprinkle capsules
FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

Monotherapy Epilepsy

Topiramate tablets, USP and Topiramate Capsules (Sprinkle) are indicated as initial monotherapy in patients 2 years of age and older with partial onset or primary generalized tonic-clonic seizures. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials [see CLINICAL STUDIES (14.1)].

Adjunctive Therapy Epilepsy

Topiramate tablets, USP and Topiramate Capsules (Sprinkle) are indicated as adjunctive therapy for adults and pediatric patients ages 2 to 16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome [see CLINICAL STUDIES (14.2)].

2. DOSAGE AND ADMINISTRATION

Epilepsy

It is not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy.

On occasion, the addition of topiramateto phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramatemay require adjustment of the dose of topiramate.

Because of the bitter taste, tablets should not be broken.

Topiramate can be taken without regard to meals.

Monotherapy Use

Adults and Pediatric Patients 10 Years and Older

The recommended dose for topiramatemonotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses. Approximately 58 % of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. The dose should be achieved by titration according to the following schedule (Table 1):

Table 1 Monotherapy Titration Schedule for Adults and Pediatric Patients 10 years and older

	Morning Dose	Evening Dose
Week 1	25 mg	25 mg
Week 2	50 mg	50 mg
Week 3	75 mg	75 mg
Week 4	100 mg	100 mg
Week 5	150 mg	150 mg
Week 6	200 mg	200 mg

Children Ages 2 to < 10 Years

Dosing of topiramate as initial monotherapy in children 2 to < 10 years of age with partial onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach [see Clinical Studies (14.1)].

Dosing in patients 2 to < 10 years is based on weight. During the titration period, the initial dose of topiramateshould be 25 mg/day administered nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day    (25 mg twice daily) in the second week. Dosage can be increased by 25 to          50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to 7 weeks of the total titration period. Based upon tolerability and seizure control, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (Table 2)

Table 2 Monotherapy Target Total Daily Maintenance Dosing for Patients 2 to < 10 Years

* Administered in two equally divided doses
Weight (kg)	Total Daily Dose (mg/day)*  Minimum Maintenance Dose	Total Daily Dose (mg/day)*  Maximum Maintenance Dose
Up to 11	150	250
12 to 22	200	300
23 to 31	200	350
32 to 38	250	350
Greater than 38	250	400

Adjunctive Therapy Use

Adults 17 Years of Age and Over - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of topiramateas adjunctive therapy in adults with partial onset seizures is 200 to 400 mg/day in two divided doses, and        400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. It is recommended that therapy be initiated at 25 to 50 mg/day followed by titration to an effective dose in increments of 25 to     50 mg/day every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day (600, 800 or 1,000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures. Daily doses above 1,600 mg have not been studied.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks [see CLINICAL STUDIES (14.1)].

Pediatric Patients Ages 2 to 16 Years – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of topiramate as adjunctive therapy for pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg/day (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.

           

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks [see CLINICAL STUDIES (14.1)].

Topiramate can be taken without regard to meals.

Administration of Topiramate Capsules (Sprinkle)

Topiramate Capsules (Sprinkle) may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use.

Patients with Renal Impairment

In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m2), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.

Geriatric Patients (Ages 65 Years and Over)

Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate < 70 mL/min/1.73 m2) is evident [see CLINICAL PHARMACOLOGY (12.3)].

Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.

Patients with Hepatic Disease

In hepatically impaired patients, topiramate plasma concentrations may be increased. The mechanism is not well understood.

3. DOSAGE FORMS AND STRENGTHS

Topiramate Tablets, USP:

25 mg, white to off-white, round-shaped, biconvex, beveled-edge, film-coated tablets debossed with "ZD 16" on one side and plain on the other side

50 mg, white to off-white, round-shaped, biconvex, beveled-edge, film-coated tablets debossed with "ZD 15" on one side and plain on the other side

100 mg, white to off-white, round-shaped, biconvex, beveled-edge, film-coated tablets debossed with "ZD 14" on one side and plain on the other side

200 mg, white to off-white, round-shaped, biconvex, beveled-edge, film-coated tablets debossed with "ZD 13" on one side and plain on the other side

Topiramate Capsules (Sprinkle):

15 mg, white to off-white pellets filled in size ‘2’ empty hard gelatin capsules with white opaque cap imprinted with "ZA63" and white opaque body imprinted with "15 mg" in black ink

25 mg, white to off-white pellets filled in size ‘1’ empty hard gelatin capsules with white opaque cap imprinted with "ZA64" and white opaque body imprinted with "25 mg" in black ink

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

Acute Myopia and Secondary Angle Closure Glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate, may be helpful.

Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.

The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramatetreatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of topiramate.

In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of < 20 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32 % for        400 mg/day, and 1 % for placebo. Metabolic acidosis has been observed at doses as low as 50 mg/day. The incidence of persistent treatment-emergent decreases in serum bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy was 15 % for 50 mg/day and 25 % for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and > 5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3 % for 400 mg/day, and 0 % for placebo and in the monotherapy trial was 1 % for 50 mg/day and 7 % for 400 mg/day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg/day.

In pediatric patients (2 to 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was 67 % for topiramate(at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and > 5 mEq/L decrease from pretreatment) in these trials was 11 % for topiramateand 0 % for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.

Although not approved for use in patients under 2 years of age with partial onset seizures, a controlled trial that examined this population revealed that topiramate produced a metabolic acidosis that is notably greater in magnitude than that observed in controlled trials in older children and adults. The mean treatment difference (25 mg/kg/day topiramate-placebo) was -5.9 mEq/L for bicarbonate. The incidence of metabolic acidosis (defined by a serum bicarbonate <20 mEq/L) was 0 % for placebo, 30 % for 5 mg/kg/day, 50 % for 15 mg/kg/day, and 45 % for 25 mg/kg/day. The incidence of markedly abnormal changes (i.e., < 17 mEq/L and > 5 mEq/L decrease from baseline of > 20 mEq/L) was 0 % for placebo, 4 % for 5 mg/kg/day, 5 % for 15 mg/kg/day, and 5 % for 25 mg/kg/day [see Use in Special Populations (8.4)].

In pediatric patients (6 to 15 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 9 % for 50 mg/day and 25 % for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and > 5 mEq/L decrease from pretreatment) in this trial was 1 % for 50 mg/day and 6 % for 400 mg/day. In adult patients (> 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 14 % for 50 mg/day and 25 % for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and > 5 mEq/L decrease from pretreatment) in this trial for adults was 1 % for 50 mg/day and 6 % for 400 mg/day.

Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials. Long-term, open-label treatment of infants/toddlers, with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in Z SCORES for length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal infants. Reductions in Z SCORES for length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4)]. Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions (5.6) Use in Specific Populations (8.1)].

Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

Table 4 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication	Placebo Patients with Events per 1000 Patients	Drug Patients with Events per 1000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events per 1000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing topiramate or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, or behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Cognitive/Neuropsychiatric Adverse Reactions

Adverse reactions most often associated with the use of topiramate were related to the central nervous system and were observed in the epilepsy populations. In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue.

Adult Patients

Cognitive-Related Dysfunction

The majority of cognitive-related adverse reactions were mild to moderate in severity, and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these reactions. Many of these reactions contributed to withdrawal from treatment [see ADVERSE REACTIONS (6)].

In the add-on epilepsy controlled trials (using rapid titration such as 100 to 200 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and 1,000 mg/day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase. Some patients who experienced one or more cognitive-related adverse reactions in the titration phase had a dose-related recurrence of these reactions in the maintenance phase.

In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day and 26% for 400 mg/day.

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (depression or mood) were dose-related for the epilepsy [see WARNINGS AND PRECAUTIONS (5.4)].

Somnolence/Fatigue

Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg/day and 1,000 mg/day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg/day. For the monotherapy epilepsy population in the 50 mg/day and 400 mg/day groups, the incidence of somnolence was dose-related (9% for the 50 mg/day group and 15% for the 400 mg/day group) and the incidence of fatigue was comparable in both treatment groups (14% each).

Additional nonspecific CNS events commonly observed with topiramate in the add-on epilepsy population included dizziness or ataxia.

Pediatric Patients

In double-blind adjunctive therapy and monotherapy epilepsy clinical studies, the incidences of cognitive/neuropsychiatric adverse reactions in pediatric patients were generally lower than observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric reactions in pediatric patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.

No patients discontinued treatment due to any adverse reactions in the adjunctive epilepsy double-blind trials. In the monotherapy epilepsy double-blind trial, 1 pediatric patient (2%) in the 50 mg/day group and 7 pediatric patients (12%) in the 400 mg/day group discontinued treatment due to any adverse reactions. The most common adverse reaction associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg/day group.

Fetal Toxicity

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see USE IN SPECIAL POPULATIONS (8.1)].

Consider the benefits and the risks of topiramate when administering this drug in women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death [see USE IN SPECIAL POPULATIONS (8.9) and PATIENT COUNSELING INFORMATION (17.8)]. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see USE IN SPECIAL POPULATIONS (8.1) and (8.9)].

Withdrawal of Antiepileptic Drugs (AEDs)

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see CLINICAL STUDIES (14)]. In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended.

Sudden Unexplained Death in Epilepsy (SUDEP)

During the course of premarketing development of topiramate tablets, 10 sudden and unexplained deaths were recorded among a cohort of treated patients (2796 subject years of exposure). This represents an incidence of 0.0035 deaths per patient year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving topiramate (ranging from 0.0005 for the general population of patients with epilepsy, to 0.003 for a clinical trial population similar to that in the topiramate program, to 0.005 for patients with refractory epilepsy).

Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use)

Hyperammonemia/Encephalopathy Without Concomitant Valproic Acid (VPA) Topiramate treatment has produced hyperammonemia (in some instances dose-related) in clinical investigational programs in very young pediatric patients (1 to 24 months) who were treated with adjunctive topiramate for partial onset epilepsy ( 8% for placebo, 10 % for 5 mg/kg/day, 0 % for 15 mg/kg/day, 9 % for 25 mg/kg/day). Topiramate is not approved as adjunctive treatment of partial onset seizures in pediatric patients less than 2 years old. In some patients, ammonia was markedly increased (≥ 50 % above upper limit of normal). In adolescent patients, the incidence of markedly increased hyperammonemia was 6 % for placebo, 6 % for 50 mg, and 12 % for 100 mg topiramate daily. The hyperammonemia associated with topiramate treatment occurred with and without encephalopathy in placebo-controlled trials, and in an open-label, extension trial. Dose-related hyperammonemia was also observed in the extension trial in pediatric patients up to 2 years old. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting.

Hyperammonemia with and without encephalopathy has also been observed in postmarketing reports in patients who were taking topiramate without concomitant valproic acid (VPA).

Hyperammonemia/Encephalopathy With Concomitant Valproic Acid (VPA)

Concomitant administration of topiramate and valproic acid (VPA) has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone based upon postmarketing reports. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction.

Although topiramate is not indicated for use in infants/toddlers (1 to 24 months) VPA clearly produced a dose-related increase in the incidence of treatment-emergent hyperammonemia (above the upper limit of normal, 0% for placebo, 12% for 5 mg/kg/day, 7% for 15 mg/kg/day, 17% for 25 mg/kg/day) in an investigational program. Markedly increased, dose-related hyperammonemia (0% for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, 8 % for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term, extension trial in these very young, pediatric patients [see USE IN SPECIFIC POPULATIONS (8.4)].

Hyperammonemia with and without encephalopathy has also been observed in postmarketing reports in patients taking topiramate with VPA.

The hyperammonemia associated with topiramate treatment appears to be more common when topiramate is used concomitantly with VPA.

Monitoring for Hyperammonemia

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

Kidney Stones

A total of 32/2086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2 to 4 times greater than expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. As in the general population, the incidence of stone formation among topiramate treated patients was higher in men. Kidney stones have also been reported in pediatric patients. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. Topiramate is not approved for pediatric patients less than 2 years old [see USE IN SPECIFIC POPULATIONS (8.4)].

An explanation for the association of topiramate and kidney stones may lie in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see WARNINGS AND PRECAUTIONS (5.4)]. The concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.

Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.

Hypothermia with Concomitant Valporic Acid (VPA) Use

Hypothermia, defined as an unintentional drop in body core temperature to          < 35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid (VPA) both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.1)]. Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

Paresthesia

Paresthesia (usually tingling of the extremities), an effect associated with the use  of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate. Paresthesia was more frequently reported in the monotherapy epilepsy trials than in the adjunctive therapy epilepsy trials. In the majority of instances, paresthesia did not lead to treatment discontinuation.

Adjustment of Dose in Renal Failure

The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Dosage adjustment may be required in patients with reduced renal function [see DOSAGE AND ADMINISTRATION (2.4)].

Decreased Hepatic Function

In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased [see Dosage and Administration (2.7)].

Monitoring: Laboratory Tests

Topiramate treatment was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies.

Topiramate treatment causes non-anion gap, hyperchloremic, metabolic acidosis manifested by a decrease in serum bicarbonate and an increase in serum chloride. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended [see WARNINGS AND PRECAUTIONS (5.3)].

Controlled trials of adjunctive topiramate treatment of adults for partial onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate, 2% placebo),markedly increased serum alkaline phosphatase (3% topiramate, 1% placebo), and decreased serum potassium (0.4 % topiramate, 0.1 % placebo). The clinical significance of these abnormalities has not been clearly established.

Changes in several clinical laboratory values (i.e.,increased creatinine, BUN, alkaline phosphatase, total protein, total eosin Phil count and decreased potassium) have been observed in a clinical investigational program in very young (< 2 years) pediatric patients who were treated with adjunctive topiramate for partial onset seizures [SEE USE IN SPECIFIC POPULATION (8.4)].

Topiramate treatment with or without concomitant valproic acid (VPA) can cause hyperammonemia with or without encephalopathy [see WARNINGS AND PRECAUTIONS (5.9)].

6. ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Acute Myopia and Secondary Angle Closure [see Warnings and Precautions (5.1)]


• Oligohidrosis and Hyperthermia [see Warnings and Precautions (5.2)]


• Metabolic Acidosis [see Warnings and Precautions (5.3)]


• Suicidal Behavior and Ideation [see Warnings and Precautions (5.4)]


• Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.5)]


• Fetal Toxicity [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]


• Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions (5.7)]


• Sudden Unexplained Death in Epilepsy (SUDEP) [see Warnings and Precautions (5.8)]


• Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use [see Warnings and Precautions (5.9)]


• Kidney Stones [see Warnings and Precautions (5.10)]


• Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions (5.11)]


• Paresthesia [see Warnings and Precautions (5.12)]

The data described in the following sections were obtained using topiramate tablets.

Monotherapy Epilepsy

Adults ≥ 16 Years

The adverse reactions in the controlled trial that occurred most commonly in adults in the 400 mg/day topiramate group and at a rate higher (> 5 %) than in the 50 mg/day group were: paresthesia, weight decrease, anorexia, somnolence, and difficulty with memory [see Table 5].

Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions.

The most common (> 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

Pediatric Patients 6 to < 16 Years of Age

The adverse reactions in the controlled trial that occurred most commonly in pediatric patients in the 400 mg/day topiramategroup and at a rate higher (> 5%) than in the 50 mg/day group were fever, weight decrease, mood problems, cognitive problems, infection, flushing, and paresthesia (see Table 5).

Approximately 14 % of the 77 pediatric patients in the 400 mg/day group who received topiramateas monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (> 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion.

Table 5 Incidence of Treatment-Emergent Adverse Reactions in Monotherapy Epilepsy Where the Rate Was at Least 2 % in Any TopiramateGroup and the Rate in the 400 mg/day TopiramateGroup Was Greater Than the Rate in the 50 mg/day TopiramateGroup for Adults (> 16 Years) and Pediatric (6 to < 16 Years) Patients in Study Topiramate-EPMN-106

*N with Female Reproductive Disorders – Incidence calculated relative to the number of females; Pediatric TPM 50 mg n=40; Pediatric TPM 400 mg n=33; Adult TPM 50 mg n=84; TPM 400 mg n=80
†Percentages calculated with the number of subjects in each group as denominator
	Age Group
	Pediatric  (6 to <16 Years)		Adult	(Age ≥16 Years )
	TOPIRAMATE Daily Dosage Group (mg/day)
Body System	(N=74)	(N=77) %†	%†	(N=159) %†
Adverse Reaction	%†	%†	%†

Spironolactone and Hydrochlorothiazide

SPIRONOLACTONE AND

HYDROCHLOROTHIAZIDE TABLETS USP

25 mg / 25 mg

Rx only

WARNING

Spironolactone, an ingredient of Spironolactone and Hydrochlorothiazide, has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). Spironolactone and Hydrochlorothiazide should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided.

Fixed-dose combination drugs are not indicated for initial therapy of edema or hypertension. Edema or hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension and edema is not static but must be reevaluated as conditions in each patient warrant.

DESCRIPTION

Spironolactone and Hydrochlorothiazide oral tablets contain:

spironolactone	25 mg
hydrochlorothiazide	25 mg

Spironolactone, an aldosterone antagonist, is 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate and has the following structural formula:

Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform.

Hydrochlorothiazide, a diuretic and antihypertensive, is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide and has the following structural formula:

Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution.

Inactive ingredients include anhydrous lactose, colloidal silicon dioxide, D&C yellow #10 lake, docusate sodium, FD&C yellow #6 lake, magnesium stearate, microcrystalline cellulose, peppermint flavor, povidone, sodium benzoate, and sodium starch glycolate.

ACTIONS / CLINICAL PHARMACOLOGY

Mechanism of action: Spironolactone and Hydrochlorothiazide is a combination of two diuretic agents with different but complementary mechanisms and sites of action, thereby providing additive diuretic and antihypertensive effects. Additionally, the spironolactone component helps to minimize the potassium loss characteristically induced by the thiazide component.

The diuretic effect of spironolactone is mediated through its action as a specific pharmacologic antagonist of aldosterone, primarily by competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Hydrochlorothiazide promotes the excretion of sodium and water primarily by inhibiting their reabsorption in the cortical diluting segment of the distal renal tubule.

Spironolactone and Hydrochlorothiazide is effective in significantly lowering the systolic and diastolic blood pressure in many patients with essential hypertension, even when aldosterone secretion is within normal limits.

Both Spironolactone and Hydrochlorothiazide reduce exchangeable sodium, plasma volume, body weight, and blood pressure. The diuretic and antihypertensive effects of the individual components are potentiated when Spironolactone and Hydrochlorothiazide are given concurrently.

Pharmacokinetics: Spironolactone is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible, together with spironolactone, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone (as tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a lowfat breakfast and blood was drawn thereafter.

Accumulation Factor:
	AUC (0–24 hr, day 15)/AUC (0–24 hr, day 1)	Mean Peak Serum Concentration	Mean (SD) Post-Steady State Half-Life
7-α-(thiomethyl) spirolactone (TMS)	1.25	391 ng/mL at 3.2 hr	13.8 hr (6.4) (terminal)
6-β-hydroxy-7-α-(thiomethyl) spirolactone (HTMS)	1.50	125 ng/mL at 5.1 hr	15.0 hr (4.0) (terminal)
Canrenone (C)	1.41	181 ng/mL at 4.3 hr	16.5 hr (6.3) (terminal)
Spironolactone	1.30	80 ng/mL at 2.6 hr	Approximately 1.4 hr (0.5) (β half-life)

The pharmacological activity of spironolactone metabolites in man is not known. However, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, TMS, and HTMS, relative to spironolactone, were 1.10, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively.

In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities.

Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile.

The effect of food on spironolactone absorption (two 100 mg spironolactone tablets) was assessed in a single dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known.

Hydrochlorothiazide is rapidly absorbed following oral administration. Onset of action of hydrochlorothiazide is observed within one hour and persists for 6 to 12 hours. Hydrochlorothiazide plasma concentrations attain peak levels at one to two hours and decline with a half-life of four to five hours. Hydrochlorothiazide undergoes only slight metabolic alteration and is excreted in urine. It is distributed throughout the extracellular space, with essentially no tissue accumulation except in the kidney.

INDICATIONS AND USAGE

Spironolactone, an ingredient of Spironolactone and Hydrochlorothiazide, has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions section). Spironolactone and Hydrochlorothiazide should be used only in those conditions described below. Unnecessary use of this drug should be avoided.

Spironolactone and Hydrochlorothiazide is indicated for:

Edematous conditions for patients with:

Congestive heart failure:

• For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures;


• The treatment of diuretic-induced hypokalemia in patients with congestive heart failure when other measures are considered inappropriate;


• The treatment of patients with congestive heart failure taking digitalis when other therapies are considered inadequate or inappropriate.

Cirrhosis of the liver accompanied by edema and/or ascites:

• Aldosterone levels may be exceptionally high in this condition. Spironolactone and Hydrochlorothiazide tablets are indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium.

The nephrotic syndrome:

• For nephrotic patients when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics do not provide an adequate response.

Essential hypertension:

• For patients with essential hypertension in whom other measures are considered inadequate or inappropriate;


• In hypertensive patients for the treatment of a diuretic-induced hypokalemia when other measures are considered inappropriate.

Usage in Pregnancy. The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developing toxemia.

Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Spironolactone and Hydrochlorothiazide tablets are indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see Precautions: Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort that is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.

CONTRAINDICATIONS

Spironolactone and Hydrochlorothiazide tablets are contraindicated in patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, or hyperkalemia, and in patients who are allergic to thiazide diuretics or to other sulfonamide-derived drugs. Spironolactone and Hydrochlorothiazide may also be contraindicated in acute or severe hepatic failure.

WARNINGS

Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with Spironolactone and Hydrochlorothiazide therapy. Excessive potassium intake may cause hyperkalemia in patients receiving Spironolactone and Hydrochlorothiazide (see Precautions: General). Spironolactone and Hydrochlorothiazide should not be administered concurrently with other potassium-sparing diuretics. Spironolactone, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when Spironolactone and Hydrochlorothiazide is given concomitantly with these drugs (see Precautions: Drug interactions).

Spironolactone and Hydrochlorothiazide should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Lithium generally should not be given with diuretics (see Precautions: Drug interactions).

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Thiazides may add to or potentiate the action of other antihypertensive drugs.

Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma.

Sulfonamide derivatives, including thiazides, have been reported to exacerbate or activate systemic lupus erythematosus.

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

PRECAUTIONS

General: All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance, e.g., hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hypokalemia or hyperkalemia.

Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal. Consequently, no potassium supplement should ordinarily be given with Spironolactone and Hydrochlorothiazide.

Concomitant administration of potassium-sparing diuretics and ACE inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin, has been associated with severe hyperkalemia.

If hyperkalemia is suspected (warning signs include paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock), an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes.

If hyperkalemia is present, Spironolactone and Hydrochlorothiazide should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis.

Hypokalemia may develop as a result of profound diuresis, particularly when Spironolactone and Hydrochlorothiazide is used concomitantly with loop diuretics, glucocorticoids, or ACTH, when severe cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmias and may exaggerate the effects of digitalis therapy. Potassium depletion may induce signs of digitalis intoxication at previously tolerated dosage levels. Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Spironolactone and Hydrochlorothiazide therapy may cause a transient elevation of BUN. This appears to represent a concentration phenomenon rather than renal toxicity, since the BUN level returns to normal after use of Spironolactone and Hydrochlorothiazide is discontinued. Progressive elevation of BUN is suggestive of the presence of preexisting renal impairment.

Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.

Dilutional hyponatremia, manifested by dryness of the mouth, thirst, lethargy, and drowsiness, and confirmed by a low serum sodium level, may be induced, especially when Spironolactone and Hydrochlorothiazide is administered in combination with other diuretics, and dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of sodium, except in rare instances when the hyponatremia is life-threatening. A true low-salt syndrome may rarely develop with Spironolactone and Hydrochlorothiazide therapy and may be manifested by increasing mental confusion similar to that observed with hepatic coma. This syndrome is differentiated from dilutional hyponatremia in that it does not occur with obvious fluid retention. Its treatment requires that diuretic therapy be discontinued and sodium administered.

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus, latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of Spironolactone and Hydrochlorothiazide may be enhanced in the post-sympathectomy patient. If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in patients on prolonged thiazide therapy.

Gynecomastia may develop in association with the use of spironolactone; physicians should be alert to its possible onset. The development of gynecomastia appears to be related to both dosage level and duration of therapy and is normally reversible when Spironolactone and Hydrochlorothiazide is discontinued. In rare instances, some breast enlargement may persist when Spironolactone and Hydrochlorothiazide is discontinued.

Information for patients: Patients who receive Spironolactone and Hydrochlorothiazide should be advised to avoid potassium supplements and foods containing high levels of potassium including salt substitutes.

Laboratory tests: Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals, particularly in the elderly and those with significant renal or hepatic impairments.

Drug interactions:

ACE inhibitors: Concomitant administration of ACE inhibitors with potassium-sparing diuretics has been associated with severe hyperkalemia.

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (e.g., oral agents, insulin): Dosage adjustment of the antidiabetic drug may be required.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur.

Pressor amines (e.g., norepinephrine): Both Spironolactone and Hydrochlorothiazide reduce the vascular responsiveness to norepinephrine. Therefore, caution should be exercised in the management of patients subjected to regional or general anesthesia while they are being treated with Spironolactone and Hydrochlorothiazide.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant may result.

Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.

Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Combination of NSAIDs, e.g., indomethacin, with potassium-sparing diuretics has been associated with severe hyperkalemia. Therefore, when Spironolactone and Hydrochlorothiazide and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Digoxin: Spironolactone has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. It may be necessary to reduce the maintenance and digitalization doses when spironolactone is administered, and the patient should be carefully monitored to avoid over- or underdigitalization.

Drug/Laboratory test interactions: Thiazides should be discontinued before carrying out tests for parathyroid function (see Precautions: General). Thiazides may also decrease serum PBI levels without evidence of alteration of thyroid function.

Several reports of possible interference with digoxin radioimmunoassays by spironolactone or its metabolites have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay specific) has been fully established.

Carcinogenesis, mutagenesis, impairment of fertility:

Spironolactone: Orally administered spironolactone has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150, and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30, 100, and 150 mg spironolactone/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females.

A dose-related (above 20 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to spironolactone and whose primary metabolite, canrenone, is also a major product of spironolactone in man) for a period of one year. In two year studies in the rat, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors.

Neither spironolactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone has been reported to be negative in some mammalian mutagenicity tests in vitro and inconclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro, inconclusive in others, and negative in still others.

In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg spironolactone/kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 mg/kg/day. When injected into female rats (100 mg/kg/day for 7 days, i.p.), spironolactone was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a two week posttreatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility, and fecundity. Spironolactone (100 mg/kg/day), administered i.p. to female mice during a two week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating.

Hydrochlorothiazide: Two year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay) and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

Pregnancy:

Teratogenic effects. Pregnancy Category C.

Hydrochlorothiazide: Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women.

Spironolactone: Teratology studies with spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryo-toxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of spironolactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. There are no adequate and well-controlled studies with Spironolactone and Hydrochlorothiazide in pregnant women. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of Spironolactone and Hydrochlorothiazide in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus.

Non-teratogenic effects

Spironolactone or its metabolites may, and hydrochlorothiazide does, cross the placental barrier and appear in cord blood. Therefore, the use of Spironolactone and Hydrochlorothiazide in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. The hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Nursing mothers: Canrenone, a major (and active) metabolite of spironolactone, appears in human breast milk. Because spironolactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric use: Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity.

Hydrochlorothiazide:

Body as a whole: Weakness.

Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics, or antihypertensive drugs).

Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialoadenitis, cramping, constipation, gastric irritation, nausea, anorexia.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

Hypersensitivity: Anaphylactic reactions, necrotizing angitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura.

Metabolic: Electrolyte imbalance (see Precautions), hyperglycemia, glycosuria, hyperuricemia.

Musculoskeletal: Muscle spasm.

Nervous system/psychiatric: Vertigo, paresthesias, dizziness, headache, restlessness.

Renal: Renal failure, renal dysfunction, interstitial nephritis (see Warnings).

Skin: Erythema multiforme, pruritus.

Special senses: Transient blurred vision, xanthopsia.

Spironolactone:

Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting.

Endocrine: Gynecomastia (see Precautions), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding. Carcinoma of the breast has been reported in patients taking spironolactone but a cause and effect relationship has not been established.

Hematologic: Agranulocytosis.

Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis.

Nervous system/psychiatric: Mental confusion, ataxia, headache, drowsiness, lethargy.

Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration.

Renal: Renal dysfunction (including renal failure).

Skin: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS).

OVERDOSAGE

The oral LD50 of spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

Acute overdosage of spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia (less commonly seen with Spironolactone and Hydrochlorothiazide because the hydrochlorothiazide component tends to produce hypokalemia), or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage.

However, because Spironolactone and Hydrochlorothiazide tablets contain both Spironolactone and Hydrochlorothiazide, the toxic effects may be intensified, and signs of thiazide overdosage may be present. These include electrolyte imbalance such as hypokalemia and/or hyponatremia. The potassium-sparing action of spironolactone may predominate and hyperkalemia may occur, especially in patients with impaired renal function. BUN determinations have been reported to rise transiently with hydrochlorothiazide. There may be CNS depression with lethargy or even coma.

Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions.

Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, Spironolactone and Hydrochlorothiazide should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution, and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis.

DOSAGE AND ADMINISTRATION

Optimal dosage should be established by individual titration of the components (see boxed Warning).

Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome). The usual maintenance dose of Spironolactone and Hydrochlorothiazide is 100 mg each of Spironolactone and Hydrochlorothiazide daily, administered in a single dose or in divided doses, but may range from 25 mg to 200 mg of each component daily depending on the response to the initial titration. In some instances it may be desirable to administer separate tablets of either spironolactone or hydrochlorothiazide in addition to Spironolactone and Hydrochlorothiazide tablets in order to provide optimal individual therapy.

The onset of diuresis with Spironolactone and Hydrochlorothiazide tablets occurs promptly and, due to prolonged effect of the spironolactone component, persists for two to three days after Spironolactone and Hydrochlorothiazide tablets are discontinued.

Essential hypertension. Although the dosage will vary depending on the results of titration of the individual ingredients, many patients will be found to have an optimal response to 50 mg to 100 mg each of Spironolactone and Hydrochlorothiazide daily, given in a single dose or in divided doses.

Concurrent potassium supplementation is not recommended when Spironolactone and Hydrochlorothiazide tablets are used in the long-term management of hypertension or in the treatment of most edematous conditions, since the spironolactone content of Spironolactone and Hydrochlorothiazide tablets is usually sufficient to minimize loss induced by the hydrochlorothiazide component.

HOW SUPPLIED

Spironolactone and Hydrochlorothiazide tablets, USP are supplied as follows:

Spironolactone and Hydrochlorothiazide tablets, 25 mg/25 mg are buff, round, unscored, debossed MP 40.

Bottles of 100	NDC 53489-144-01
Bottles of 500	NDC 53489-144-05
Bottles of 1000	NDC 53489-144-10

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature]

DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

Manufactured by:

MUTUAL PHARMACEUTICAL COMPANY, INC.

Philadelphia, PA 19124 USA

Rev 03, September 2011

PRINCIPAL DISPLAY PANEL - 25 mg Bottle Label

MP

NDC 53489-144-01

SPIRONOLACTONE AND

HYDROCHLOROTHIAZIDE TABLETS USP

25 mg/25 mg

100 TABLETS

Rx only

MUTUAL PHARMACEUTICAL CO., INC.

PHILADELPHIA, PA 19124 USA

Spironolactone and Hydrochlorothiazide  Spironolactone and Hydrochlorothiazide  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 53489-144 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Spironolactone (Spironolactone) Spironolactone 25 mg Hydrochlorothiazide (Hydrochlorothiazide) Hydrochlorothiazide 25 mg

Inactive Ingredients Ingredient Name Strength anhydrous lactose   silicon dioxide   D&C yellow No. 10   docusate sodium   FD&C yellow no. 6   Aluminum Oxide   magnesium stearate   cellulose, microcrystalline   peppermint   povidone   sodium benzoate   Sodium Starch Glycolate Type A Potato

Product Characteristics Color WHITE (off-white, buff) Score no score Shape ROUND Size 10mm Flavor PEPPERMINT Imprint Code MP;40 Contains

Packaging # NDC Package Description Multilevel Packaging 1 53489-144-01 100 TABLET In 1 BOTTLE None 2 53489-144-05 500 TABLET In 1 BOTTLE None 3 53489-144-10 1000 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA089534	07/02/1987

Labeler - Mutual Pharmaceutical Company, Inc. (121735955)

Revised: 10/2011Mutual Pharmaceutical Company, Inc.

More Spironolactone and Hydrochlorothiazide resources

• Spironolactone and Hydrochlorothiazide Side Effects (in more detail)
• Spironolactone and Hydrochlorothiazide Dosage
• Spironolactone and Hydrochlorothiazide Use in Pregnancy & Breastfeeding
• Drug Images
• Spironolactone and Hydrochlorothiazide Drug Interactions
• Spironolactone and Hydrochlorothiazide Support Group
• 2 Reviews for Spironolactone and Hydrochlorothiazide - Add your own review/rating

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• Ascites
• Edema
• Heart Failure
• High Blood Pressure
• Nephrotic Syndrome

Thiola

Pronunciation: tye-oh-PRO-nin
Generic Name: Tiopronin
Brand Name: Thiola

Thiola is used for:

Preventing kidney stone formation in certain patients.

Thiola is a chelating agent. It works by removing extra cystine (the cause of kidney stones) from the urine, which keeps the kidney stones from forming.

Do NOT use Thiola if:

• you are allergic to any ingredient in Thiola


• you are breast-feeding


• you have a history of anemia, low white blood cell counts, or low platelet counts resulting from the use of Thiola

Contact your doctor or health care provider right away if any of these apply to you.

Before using Thiola:

Some medical conditions may interact with Thiola. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant or planning to become pregnant


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have anemia, bleeding in the lungs, low white blood cell counts, low platelet counts, or muscle weakness

Some MEDICINES MAY INTERACT with Thiola. However, no specific interactions with Thiola are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Thiola may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Thiola:

Use Thiola as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Thiola on an empty stomach at least 1 hour before or 2 hours after eating.


• Drink at least ten 10-ounce glasses of water each day, including 2 glasses with each meal and at bedtime. You will probably wake up at night to urinate, and you should drink 2 more glasses before returning to bed. Drink extra fluids if you have excessive sweating or urination.


• When you first start taking Thiola, it may cause an increase in urine or in frequency of urination. To prevent this from affecting sleep, try not to take any dose later than 6 pm.


• If you miss a dose of Thiola, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Thiola.

Important safety information:

• Thiola may reduce the number of clot-forming cells (platelets) in your blood. To prevent bleeding, avoid situations in which bruising or injury may occur. Report any unusual bleeding, bruising, blood in stools, or dark, tarry stools to your doctor.


• Be sure to follow the diet and exercise program prescribed by your health care provider.


• LAB TESTS, including blood cell counts and liver function tests, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• Thiola is not recommended for use in CHILDREN younger than 9 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Thiola may cause harm to the fetus. If you become pregnant, discuss with your doctor the benefits and risks of using Thiola during pregnancy. Thiola is excreted in breast milk. Do not breast-feed while taking Thiola.

Possible side effects of Thiola:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Appetite loss; changes in taste; diarrhea; drying of skin; gas; loss of appetite; nausea; soft stools; stomach bloating; stomach pain; vomiting; wrinkling or crumbling of skin.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); fever; joint pain; muscle weakness; red rash with fever; sore throat; unusual bleeding or bruising; yellowing of skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Thiola side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Thiola:

Store Thiola at room temperature, between 59 and 77 degrees F (15 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Thiola out of the reach of children and away from pets.

General information:

• If you have any questions about Thiola, please talk with your doctor, pharmacist, or other health care provider.


• Thiola is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Thiola. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Thiola resources

• Thiola Side Effects (in more detail)
• Thiola Use in Pregnancy & Breastfeeding
• Thiola Support Group
• 0 Reviews for Thiola - Add your own review/rating

• Thiola Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Thiola with other medications

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AmLactin Foot Cream Therapy

Generic Name: ammonium lactate topical (a MOE nee um LAK tate)

Brand Names: Amlactin, AmLactin Foot Cream Therapy, Amlactin XL, Kerasal AL, Lac-Hydrin, Lac-Hydrin 5, Laclotion

What is ammonium lactate?

Ammonium lactate is a combination of lactic acid and ammonium hydroxide. Ammonium lactate is a moisturizer.

Ammonium lactate is used to treat dry, scaly, itchy skin.

Ammonium lactate may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about ammonium lactate?

Do not apply ammonium lactate to your face unless your doctor has told you to. Avoid getting this medication in your mouth or eyes. If it does get into any of these areas, rinse with water. Do not apply ammonium lactate topical after shaving or use it on sunburned, windburned, dry, chapped, irritated, or broken skin. Avoid exposure to sunlight or artificial UV rays (sunlamps or tanning beds). Ammonium lactate can make your skin more sensitive to sunlight and sunburn may result. Use a sunscreen (minimum SPF 15) and wear protective clothing if you must be out in the sun.

Call your doctor if your skin condition does not improve or if it gets worse even with ammonium lactate treatment.

Stop using the medication and call your doctor if you have severe burning, stinging, redness, or peeling of the skin treated with ammonium lactate.

What should I discuss with my healthcare provider before using AmLactin Foot Cream Therapy (ammonium lactate topical)?

You should not use this medication if you are allergic to ammonium lactate.

Ammonium lactate may be more likely to cause skin irritation in people who have fair or sensitive skin.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether ammonium lactate passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Ammonium lactate should not be used on a child without the advice of a doctor.

How should I apply ammonium lactate?

Use this medication exactly as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Shake the lotion form of this medication well just before using it.

Ammonium lactate is usually applied twice a day. Follow your doctor's instructions.

Wash your hands before and after applying this medication, unless you are using it to treat a hand condition. Do not apply ammonium lactate to your face unless your doctor has told you to.

Call your doctor if your skin condition does not improve or if it gets worse even with ammonium lactate treatment.

Store ammonium lactate at room temperature away from moisture and heat.

What happens if I miss a dose?

Apply the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

An overdose of ammonium lactate is unlikely to occur.

What should I avoid while using ammonium lactate?

Avoid getting this medication in your mouth or eyes. If it does get into any of these areas, rinse with water. Do not apply ammonium lactate topical after shaving or use it on sunburned, windburned, dry, chapped, irritated, or broken skin. Avoid exposure to sunlight or artificial UV rays (sunlamps or tanning beds). Ammonium lactate can make your skin more sensitive to sunlight and sunburn may result. Use a sunscreen (minimum SPF 15) and wear protective clothing if you must be out in the sun.

Ammonium lactate side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using the medication and call your doctor if you have severe burning, stinging, redness, or peeling of the skin treated with ammonium lactate.

Less serious side effects may include:

• 
  

  mild skin peeling or dryness;

  
  


• 
  

  mild skin redness or irritation;

  
  


• 
  

  bruising or other discoloration; or

  
  


• 
  

  darkening of the treated skin.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect ammonium lactate?

It is not likely that other drugs you take orally or inject will have an effect on topically applied ammonium lactate. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More AmLactin Foot Cream Therapy resources

• AmLactin Foot Cream Therapy Side Effects (in more detail)
• AmLactin Foot Cream Therapy Use in Pregnancy & Breastfeeding
• AmLactin Foot Cream Therapy Support Group
• 2 Reviews for AmLactin Foot Therapy - Add your own review/rating

• AmLactin Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• LAClotion Prescribing Information (FDA)


• Lac-Hydrin Prescribing Information (FDA)

Compare AmLactin Foot Cream Therapy with other medications

• Dry Skin
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Where can I get more information?

• Your pharmacist can provide more information about ammonium lactate topical.

See also: AmLactin Foot Therapy side effects (in more detail)

Ipide

Ipide may be available in the countries listed below.

Ingredient matches for Ipide

Indapamide

Indapamide is reported as an ingredient of Ipide in the following countries:

• Bangladesh

International Drug Name Search

Zovia

Pronunciation: e-thye-noe-DYE-ole/ETH-in-il ess-trah-DYE-ole
Generic Name: Ethynodiol/Ethinyl Estradiol
Brand Name: Examples include Demulen and Zovia

Cigarette smoking while taking Zovia increases the risk of serious heart problems. The risk increases with age (older than 35 years) and with heavy smoking (15 or more cigarettes per day). Patients who use Zovia are strongly advised not to smoke.

Zovia is used for:

Preventing pregnancy. It may also be used for other conditions as determined by your doctor.

Zovia is an estrogen/progestin combination. It works by preventing the release of eggs from the ovaries and thereby preventing pregnancy.

Do NOT use Zovia if:

• you are allergic to any ingredient in Zovia


• you are pregnant or think you may be pregnant


• you have blood clots in the legs, lungs, or eyes; or a history of heart attack, chest pain, or stroke


• you have known or suspected breast cancer or cancer of the lining of the uterus, cervix, or vagina, or have had vaginal bleeding of unknown causes


• you have a liver tumor or active liver disease, or a history of yellowing of the eyes or skin during pregnancy or previous birth control use


• you have headaches with neurological symptoms or will be on bed rest for a long period following surgery

Contact your doctor or health care provider right away if any of these apply to you.

Before using Zovia:

Some medical conditions may interact with Zovia. Tell your health care provider if you have any medical conditions, especially if any of the following apply to you:

• if you are planning to become pregnant or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have high blood pressure; high cholesterol, triglycerides, or calcium levels; have pancreatitis or gallbladder problems; or are obese


• if you have breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram, endometriosis or endometrial carcinomas, uterine fibroids, or irregular or scanty menstrual periods


• if you have diabetes, headaches, migraine headaches, epilepsy, or a history of mental depression


• if you are having surgery


• if you are a heavy smoker (15 or more cigarettes per day), especially if you are older than 35 years of age

Some MEDICINES MAY INTERACT with Zovia. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Azole antifungals (eg, itraconazole), aprepitant, bosentan, barbiturates (eg, phenobarbital), carbamazepine, felbamate, griseofulvin, HIV protease inhibitors (eg, ritonavir), hydantoins (eg, phenytoin), modafinil, nevirapine, penicillins (eg, amoxicillin), rifampin, St. John's wort, tetracyclines (eg, doxycycline), topiramate, and troglitazone because they may decrease Zovia's effectiveness. Alternative forms of birth control are strongly recommended when taking any of these medicines along with this birth control medicine.


• Beta-blockers (eg, atenolol), selegiline, theophyllines (eg, aminophylline), and troleandomycin because the risk of their side effects may be increased by Zovia


• Lamotrigine because its effectiveness may be decreased by Zovia

This may not be a complete list of all interactions that may occur. Ask your health care provider if Zovia may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Zovia:

Use Zovia as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Zovia. Talk to your pharmacist if you have questions about this information.


• Take Zovia by mouth with or without food.


• To achieve maximum effectiveness of Zovia, it must be taken every day (every 24 hours) and at the same time each day.


• Remember to take all of the pills in the pack. Do not skip any doses.


• Be sure to have an extra full pack of this medication available at all times.


• If you miss 1 dose of Zovia, take it as soon as you remember. Take your next dose at the regular time. This means you may take 2 doses on the same day. You do not need to use a backup method of birth control if you only miss 1 pill. If you miss more than 1 active dose of Zovia, read the extra patient leaflet that comes with your medicine or contact your doctor for instructions. You must use a backup method of birth control if you miss more than 1 active dose of Zovia. If you are not sure about how to handle missed doses, use an extra form of birth control (eg, condoms) and talk with your doctor.

Ask your health care provider any questions you may have about how to use Zovia.

Important safety information:

• Zovia may cause dizziness or changes in vision. These effects may be worse if you take it with alcohol or certain medicines. Use Zovia with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• If you miss your period during the week of inactive pills, call your doctor immediately. A missed period may indicate that you are pregnant.


• Zovia may cause dark skin patches on your face. Exposure to the sun may make these patches darker. If patches develop, use a sunscreen or protective clothing when exposed to the sun, sunlamps, or tanning booths.


• If you wear contact lenses and you develop problems with them or with your vision, contact your doctor as soon as possible.


• Follow your doctor's instructions for examining your own breasts, and report any lumps immediately.


• Zovia may interfere with certain lab tests. Be sure your doctor and lab personnel know you are using Zovia.


• If you will be having surgery or will be confined to a chair or bed for a long period of time (such as a long plane flight), notify your doctor 3 to 4 weeks beforehand. Special precautions may need to be taken in these circumstances while you are taking Zovia.


• Bleeding or spotting may occur while taking Zovia. Do not stop taking Zovia if this occurs. If bleeding or spotting continues for more than 7 days or is heavy, contact your doctor.


• Smoking cigarettes while using Zovia may increase your risk of stroke, heart attack, blood clots, high blood pressure, or other diseases of the heart and blood vessels.


• Taking certain antibiotics or anticonvulsants while you are using Zovia, or vomiting or diarrhea may decrease the effectiveness of Zovia. To prevent pregnancy, use an additional form of birth control (such as condoms, spermicide, diaphragm) until your next period. If you have any questions, contact your doctor or pharmacist.


• Use of Zovia will not prevent the spread of sexually transmitted diseases (STDs).


• You should usually not start taking Zovia within 4 weeks after giving birth. Discuss any questions or concerns you have with your doctor.


• Lab tests will be required while you are taking Zovia. You will need to have follow-up exams at least once per year. Be sure to keep all doctor and lab appointments.


• Zovia should not be used in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Do not take Zovia if you are pregnant. If you think you may be pregnant, contact your doctor right away. Zovia is found in breast milk. Do not breast-feed while taking Zovia.

Possible side effects of Zovia:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Breast tenderness or enlargement; changes in appetite; changes in weight; dizziness; headache; loss of scalp hair; nausea; nervousness; stomach cramps or bloating; vaginal spotting or breakthrough bleeding; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloating; breast lumps; breast tenderness; calf/leg pain or swelling; changes in vision; chest pain or heaviness in the chest; coughing up blood; dark urine or light-colored bowel movements; dizziness or fainting; fever; missed menstrual period; mood/mental changes; numbness of an arm or leg; persistent or recurrent abnormal vaginal bleeding; severe pain or tenderness in the stomach area; shortness of breath; sleeplessness; slurred speech; sudden severe headache (migraine); sudden shortness of breath; swelling of fingers or ankles; unusual vaginal itching, discharge, or odor; vomiting; weakness or fatigue; weakness or numbness in the arm or leg; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Zovia side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include nausea or vomiting; vaginal bleeding.

Proper storage of Zovia:

Store Zovia at room temperature, below 86 degrees F (30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Zovia out of the reach of children and away from pets.

General information:

• If you have any questions about Zovia, please talk with your doctor, pharmacist, or other health care provider.


• Zovia is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Zovia. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Zovia resources

• Zovia Side Effects (in more detail)
• Zovia Use in Pregnancy & Breastfeeding
• Zovia Drug Interactions
• Zovia Support Group
• 14 Reviews for Zovia - Add your own review/rating

• Kelnor Prescribing Information (FDA)


• Kelnor Concise Consumer Information (Cerner Multum)

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Clofarabine

Pronunciation: kloe-FAR-a-been
Generic Name: Clofarabine
Brand Name: Clolar

Clofarabine is used for:

Treating certain types of leukemia in children and adolescents who have had at least 2 previous treatment regimens of medicine.

Clofarabine is a form of antimetabolite chemotherapy. It works by blocking cancer cell growth, which results in death of the cancer cell.

Do NOT use Clofarabine if:

• you are allergic to any ingredient in Clofarabine


• you are taking medicines that may affect the kidney, such as aminoglycoside antibiotics (eg, gentamicin), amphotericin B, cyclosporine, nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen), tacrolimus, and vancomycin. Ask your doctor if you are unsure whether any of your medicines might affect your kidneys


• you are taking medicines that may affect the liver, such as acetaminophen, certain medicines for HIV infection, isoniazid, ketoconazole, and methotrexate. Ask your doctor if you are unsure whether any of your medicines might affect your liver

Contact your doctor or health care provider right away if any of these apply to you.

Before using Clofarabine:

Some medical conditions may interact with Clofarabine. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have high or low blood pressure, kidney problems, liver problems, or heart problems


• if you have an infection, certain blood problems (eg, low white blood cell levels, low platelet levels), or bone marrow problems


• if you have previously had a hematopoietic stem cell transplant (HSCT)

Some MEDICINES MAY INTERACT with Clofarabine. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Medicines that may affect your heart function or blood pressure because the side effects of Clofarabine such as low blood pressure or heart effects may be increased. Ask your doctor if you are unsure whether any of your medicines might affect your heart function or blood pressure


• Medicines that affect your kidneys or liver because the risk of Clofarabine's side effects may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Clofarabine may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Clofarabine:

Use Clofarabine as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Clofarabine is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Clofarabine at home, a health care provider will teach you how to use it. Be sure you understand how to use Clofarabine. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Do not use Clofarabine if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.


• Do not administer any other medicines through the same intravenous line as Clofarabine.


• If Clofarabine accidentally spills on your skin, wash it off immediately with soap and water.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• If you miss a dose of Clofarabine, contact your doctor immediately.

Ask your health care provider any questions you may have about how to use Clofarabine.

Important safety information:

• Clofarabine may cause drowsiness, dizziness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Clofarabine with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• If vomiting or diarrhea occurs, you will need to take care not to become dehydrated. Contact your doctor for instructions.


• Notify your doctor immediately if you experience symptoms of dehydration such as dry mouth; decreased urination; unusual thirst; weakness; unusual drowsiness or lethargy; muscle pain, cramps, or weakness; severe dizziness or fainting; or rapid heartbeat.


• Clofarabine may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.


• Clofarabine may lower the ability of your body to fight infection. Avoid contact with people who have colds or infections. Tell your doctor if you notice signs of infection like fever, sore throat, rash, or chills.


• Proper dental care is important while you are taking Clofarabine. Brush and floss your teeth and visit the dentist regularly.


• Tell your doctor or dentist that you take Clofarabine before you receive any medical or dental care, emergency care, or surgery.


• Women who may become pregnant must use an effective form of birth control while they take Clofarabine. If you have questions about effective birth control, talk with your doctor.


• Men who use Clofarabine should always use a condom when having sex with a woman who may become pregnant. Do this for as long as you use Clofarabine.


• Lab tests, including blood counts, blood pressure, lung function, liver function, kidney function, and blood uric acid levels, may be performed while you use Clofarabine. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Safety and effectiveness of Clofarabine have not been established in ADULTS.


• PREGNANCY AND BREAST-FEEDING: Clofarabine has been shown to cause harm to the fetus. Do not become pregnant while you are using it. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Clofarabine while you are pregnant. Do not breast-feed while taking Clofarabine.

Possible side effects of Clofarabine:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Back pain; constipation; cough; decreased weight; diarrhea; dizziness; drowsiness; dry or irritated skin; flushing; gum bleeding; headache; itching; joint or muscle pain or weakness; loss of appetite; minor pain, swelling, or redness at the injection site; nausea; stomach pain; swelling or soreness of the mouth; tiredness or weakness; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blistering or severe swelling or pain at the injection site; blood in the urine; cloudy or dark urine; decreased urination; fainting; fast breathing; fast or irregular heartbeat; fever, chills, or sore throat; mental or mood changes; nosebleed; persistent cough; pneumonia; red, swollen, blistered, or peeling skin; severe dizziness or lightheadedness; severe or persistent tiredness or weakness; severe or persistent vomiting or diarrhea; shaking; shortness of breath; small red spots under the skin; swelling of arms or legs; tingling, pain, redness, or swelling of the palms of the hands or soles of the feet; unusual bleeding or easy bruising; unusual tiredness or weakness; unusually pale skin; white patches in the mouth; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Clofarabine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include rash; vomiting.

Proper storage of Clofarabine:

Store undiluted vials of Clofarabine at 77 degrees F (25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. After diluting, Clofarabine may be stored at room temperature and must be used within 24 hours. Keep Clofarabine out of the reach of children and away from pets.

General information:

• If you have any questions about Clofarabine, please talk with your doctor, pharmacist, or other health care provider.


• Clofarabine is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Clofarabine. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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