Ovulation is the result of a maturation process that occurs in the hypothalamic-pituitary-ovarian (HPO) axis and is orchestrated by a neuroendocrine cascade terminating in the ovaries. Any alteration results in a failure to release a mature ovum, leading to anovulatory cycles. Anovulation may manifest in a variety of clinical presentations, from luteal insufficiency to oligomenorrhea.
Anovulation is a not a disease but a sign, in much the same way that polycystic ovaries are the manifestation of a much larger disease process.
Pathophysiology
Luteinizing hormone (LH) is the physiologic signal necessary for ovulation, which is mediated by a concomitant surge in estrogen. As the follicle grows through accumulation of follicular fluid, the cohort of granulosa cells acquire the necessary receptors to respond to LH with increased formation of cyclic adenosine monophosphate (cAMP). Generally speaking, approximately 16-24 hours after the LH peak, ovulation occurs with the extrusion of a mature graafian follicle and the formation of the corpus luteum (Speroff, 1999). These events are the culmination of a well-coordinated interplay between hormones and their appropriate receptors and proteolytic enzymes and prostaglandins acting in concert with one another, all directed by the HPO axis.
The system is so sensitive that even the slightest alteration in any of these factors can disrupt its fluidity and lead to anovulation.
When problems arise at any of the many different levels involved in the normal menstrual cycle, it is sometimes helpful to separate the levels by organ system. The hypothalamus and the anterior pituitary can be considered the neuroendocrine components by virtue of their proximity to each another, while the ovaries are a separate compartment. The third aspect that can be defective is the signaling process that occurs between these 2 areas (Speroff, 1999).
The initial stimulus must come from the hypothalamus in the form of gonadotropin-releasing hormone (GnRH); this decapeptide must be secreted in a pulsatile fashion within a critical range. For example, sexual maturity is not attained until the onset of regular ovulatory cycles, which may take months to years to occur. This maturation process is orchestrated by a neuroendocrine cascade and modified by autocrine and paracrine events in the ovaries, in which GnRH is the principal mediator (Spence, 1997).
Any alteration in the GnRH pulse generator alters the hormonal milieu necessary for gonadotropin secretion and eventual response at the level of the ovary. Several entities (eg, hyperprolactinemia) are known to cause this type of dysregulation. Increasing levels of prolactin can cause a woman to progress from a deficient luteal phase to overt amenorrhea, usually associated with complete GnRH suppression. More common causes of dysregulation include stress, anxiety, and eating disorders, which are also associated with an inhibition of normal GnRH pulsatility through excessive hypothalamic activity of corticotrophin-releasing hormone and stimulation of beta-endorphins (Yen, 1999).
How polycystic ovary syndrome (PCOS) is associated with anovulatory cycles has not been completely elucidated. Two associations with this disease entity are theorized to be at least somewhat responsible for its development. The first is the persistent elevation of LH levels in these patients; the second is the apparent arrest of antral follicle development at the 5- to 10-mm stage and consequent failure to enter the preovulatory phase of the cycle (Franks, 1998). This evidence indicates that the disturbance is mainly a central defect that initiates the cascade of events leading to its onset.
Similarly, any condition, whether primary or secondary, that results in either a persistent elevation or an insufficient attainment of estrogen levels can inhibit ovulation through a disruption of the mechanisms that induce the LH surge. In order to achieve the corresponding changes within the cycle, estradiol levels must rise and fall appropriately (Speroff, 1999).
Frequency
United States
Almost all women experience anovulatory cycles at some point in their reproductive lives. Yet, to attempt to determine the frequency of chronic anovulation in the general population is quite difficult because of underreporting. Estimates of chronic anovulation rates range from 6-15% of women during the reproductive years.
Interestingly, a recent article introduced a certain subset of the population as being at an increased risk for anovulatory disorders, stating that reproductive endocrine disorders, such as PCOS, hypothalamic amenorrhea, premature menopause, and hyperprolactinemia, are reportedly more common in women with epilepsy than in the general female population. The article further elaborates on the frequency of PCOS in patients who endure epilepsy independent of the use of antiepileptic therapy (Rasgon, 2004).
Mortality/Morbidity
Morbidities associated with chronic anovulation include hyperinsulinemia, insulin resistance, early onset of type 2 diabetes mellitus, dyslipidemia, cardiovascular disease, and infertility.
Race
In one study, the frequency of anovulation was greater among white women (9 [14.3%] of 63) than black women (4 [7.1%] of 56) or Hispanic women (7 [6.9%] of 102), although these differences were not statistically significant (Haiman, 2002).
Sex
Obviously, anovulation occurs only in women of reproductive age.
Age
Anovulation is physiologic at the extremes of reproductive age. During menarche, absence of ovulation is due to immaturity of the HPO axis, leading to an uncoordinated secretion of GnRH (pulsatility).
During perimenopause, ovarian factors and a dysregulation of feedback mechanisms are responsible.
When anovulation occurs outside of the perimenarchal or perimenopausal years, extrinsic and intrinsic causes must be excluded.
Treatment
The medical management of anovulation is complex because it entails initiating a multitiered approach to patient care. First and foremost, the clinician should be well acquainted with the most common etiologies and able to rule them out, specifically those that can pose serious dangers to a patient's immediate health. Luckily, anovulation usually manifests in a clinical setting geared toward the treatment of chronic diseases and conditions, which provides the precision necessary for an accurate diagnosis. Despite this, patients often have a history of multiple doctor visits because of inadequate or unsuccessful treatment by other physicians secondary to a misdiagnosis. The care of these patients must be tailored to their individual presentations and the specific disease entities responsible for anovulation. A holistic approach, consultation with other specialists, and routine follow-up should be the rule, not the exception.Medical Care
Surgical care is usually indicated to resolve the underlying cause for the anovulation, typically when medical therapy has failed. Surgery is also indicated in rare cases, such as a macroadenoma of the pituitary with unrelenting growth eliciting severe symptoms (eg, headaches, bitemporal hemianopsia, diplopia). In the event of a benign or malignant neoplasm of ovarian or adrenal origin, exploratory laparotomy, resection, and staging are indicated. Ovarian drilling and ovarian wedge resection are other surgical modalities used in the treatment of anovulation due to PCOS, with a spontaneous ovulation rate of more than 80% after the procedure. While dilation and curettage is never first-line therapy for acute bleeding, practitioners are sometimes left with no other option. In even rarer cases, hysterectomy may be the only solution to the profound anemia stemming from acute blood loss. Bariatric surgery has been advocated in the surgical treatment of severe obesity when accompanied by medical complications in which weight loss could be curative. Gastroplasty, vertical banded gastroplasty, gastric banding, and vertical stapling are commonly used but are less effective than the roux-en-Y gastric bypass. Typically patients with a BMI greater than 40 are candidates for surgery, assuming past attempts at medical treatment have failed, although patients with a BMI of 35-40 and underlying life-threatening medical problem may be considered as well (Goldman, 2004)Surgical Care
Consultations
When considering a specific diet in the setting of anovulation, the principal focus must be in reference to the endocrinologic and metabolic derangements observed in PCOS. Therefore, a well-structured low-carbohydrate/low-cholesterol regimen is imperative because of the insulin resistance and cardiovascular risks commonly occurring in these patients. The effectiveness of organized weight loss programs such as Weight Watchers, Curves, or Jenny Craig has been well documented to improve the recidivism rate in overweight patients attempting to lose weight when done in conjunction with counseling and support group initiatives. Cardiovascular exercise helps offset the inherent risks associated with PCOS. Weight-bearing exercise should be recommended for patients with hypoestrogenic states, such as premature ovarian failure, when estrogen replacement is a contraindicated.Diet
Activity
Medication
Medical therapy of anovulation should be directed at reversal of the primary underlying cause and tailored to the individual patient.
Drug Category: Ovulation stimulators
Are used for ovulation induction.
| Drug Name | Clomiphene citrate (Serophene, Clomid, Milophene) |
|---|---|
| Description | Stimulates release of pituitary gonadotropins. Acts as an antiestrogen to decrease negative estrogen feedback on hypothalamus. In addition, may have effects on pituitary gland and ovaries and can induce ovulation in women with hypothalamic amenorrhea. Improves folliculogenesis and, therefore, ovarian function during luteal phase. |
| Adult Dose | 50-100 mg PO qd for 5 d; not to exceed 6 mo |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; liver disease; abnormal uterine bleeding; uncontrolled thyroid or adrenal dysfunction |
| Interactions | Danazol may reduce response |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Visual symptoms and abdominal pain may occur |
Drug Category: Thyroid products
Are used to correct hypothyroidism.
| Drug Name | Levothyroxine (Synthroid, Levoxyl, Levothroid) |
|---|---|
| Description | If luteal phase dysfunction is caused by hypothyroidism, correction of endocrine disease results in normal luteal phase. |
| Adult Dose | 12.5-50 mcg PO qd; increase by 25-50 mcg/d q2-4wk to maximum 100-200 mcg/d |
| Pediatric Dose | Neonate to 6 months: 25-50 mcg PO qd 6-12 months: 50-75 mcg PO qd 1-5 years: 75-100 mcg PO qd 6-12 years: 100-150 mcg PO qd >12 years: 150 mcg PO qd |
| Contraindications | Documented hypersensitivity; uncorrected adrenal insufficiency |
| Interactions | Cholestyramine may decrease liothyronine absorption; estrogens may decrease response to thyroid hormone therapy in patients with nonfunctioning thyroid glands; effect of anticoagulants increased when administered with liothyronine; activity of some beta-blockers may decrease when hypothyroid patient is converted to a euthyroid state |
| Pregnancy | A - Safe in pregnancy |
| Precautions | Caution in angina pectoris or cardiovascular disease; periodically monitor thyroid status |
Drug Category: Oral contraceptives
Are used for hormone replacement.
| Drug Name | Ethinyl estradiol and norethindrone (Ortho-Novum, Ovcon 35, Ovcon 50) |
|---|---|
| Description | In young females, low-dose PO contraception generally is an excellent method of hormone replacement. Any low-dose combination pill with 35 mcg of ethinyl estradiol or less or any progestin is appropriate. Also useful because, on occasion, these women may spontaneously ovulate and become pregnant. |
| Adult Dose | Schedule 1 (Sunday starter): Begin dose on first Sunday after onset of menstruation or on Sunday if menstrual period starts on Sunday 21-tab package: 1 tab PO qd for 21 d followed by 7 d off medication; new course begins on 8th d after taking last tab 28-tab package: 1 tab PO qd without interruption Schedule 2 (day 1 starter): Start dose on day 1 of menstrual cycle 21-tab package: 1 tab PO qd for 21 d followed by 7 d off medication; begin new course on day 8 after taking last tab; continue dosing cycle if 1 period is missed; pregnancy test required if 2 periods are missed |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; endometrial and hepatic cancer; thromboembolic disorders; undiagnosed vaginal bleeding; smokers >35 y; cardiovascular disease |
| Interactions | Phenobarbital, phenytoin, paramethadione, carbamazepine, troglitazone, rifampicin, and griseofulvin induce enzymes that decrease levels of contraceptive steroids; PO anticoagulants may increase thromboembolic potential; antibiotics may alter GI flora and cause a reduction in absorption of PO contraceptives, which may reduce efficacy |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Caution in patients diagnosed with hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease |
| Drug Name | Ethinyl estradiol/norgestimate (Ortho-Prefest, Ortho TriCyclen, Ortho-Cyclen) |
|---|---|
| Description | In young females, low-dose PO contraception generally is an excellent method of hormone replacement. Any low-dose combination pill with 35 mcg of ethinyl estradiol or less or any progestin is appropriate. Also useful because, on occasion, these women may spontaneously ovulate and become pregnant. |
| Adult Dose | Schedule 1 (Sunday starter): Begin dose on first Sunday after onset of menstruation; start Sunday if menstrual period starts on Sunday 21-tab package: 1 tab PO qd for 21 d followed by 7 d off medication; new course begins on day 8 after taking last tab 28-tab package: 1 tab PO qd without interruption Schedule 2 (day 1 starter): Start dose on day 1 of menstrual cycle 21-tab package: 1 tab PO qd for 21 d followed by 7 d off medication; begin new course on day 8 after taking last tab; continue dosing cycle if 1 period is missed; pregnancy test required if 2 periods are missed |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; endometrial and hepatic cancer; thromboembolic disorders; undiagnosed vaginal bleeding; smokers >35 y; cardiovascular disease |
| Interactions | Phenobarbital, phenytoin, paramethadione, carbamazepine, troglitazone, rifampicin, and griseofulvin induce enzymes that decrease levels of contraceptive steroids; PO anticoagulants may increase thromboembolic potential; antibiotics may alter GI flora and cause a reduction in absorption of PO contraceptives, which may reduce efficacy |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Caution in patients diagnosed with hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease |
Drug Category: Bisphosphonate derivatives
Are analogs of pyrophosphate and act by binding to hydroxyapatite in bone matrix, thereby inhibiting dissolution of crystals. Prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.
| Drug Name | Alendronate (Fosamax) |
|---|---|
| Description | Inhibits bone resorption via actions on osteoclasts or osteoclast precursors. Used to treat osteoporosis in both men and women. May reduce bone resorption and incidence of fracture at spine, hip, and wrist by approximately 50%. Should be taken with a large glass of water at least 30 min before eating and drinking to maximize absorption. Because of possible esophageal irritation, patients must remain upright after taking the medication. Since it is renally excreted, not recommended in patients with moderate-to-severe renal insufficiency (ie, CrCl <30> 3 mg/dL); use in perirenal transplantation is limited. |
| Adult Dose | Prophylaxis: 5 mg PO qd; alternatively, 35 mg PO qwk Treatment: 10 mg PO qd; alternatively, 70 mg PO qwk |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; hypocalcemia; abnormalities of the esophagus; inability to stand upright for 30 min |
| Interactions | None reported |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Must be taken at least 30 min before first food, beverage, or medication of the day and should be taken with large amounts of water; caution in renal impairment |
Drug Category: Oral antidiabetic agents
May increase glucose uptake in peripheral tissues.
| Drug Name | Metformin (Glucophage) |
|---|---|
| Description | Reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in the peripheral tissues (muscle and adipocytes). Major drug used in obese patients who have type 2 diabetes mellitus. |
| Adult Dose | Initial: 500 mg PO bid Maintenance: 850 mg PO tid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; acute myocardial infarction; septicemia; renal disease |
| Interactions | Diuretics, thyroid products, PO contraceptives, phenytoin, calcium channel–blocking drugs; phenothiazines may decrease effects; cimetidine may increase levels |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in renal insufficiency; discontinue therapy before performing any surgical procedures; impaired liver function |
Drug Category: Antiandrogens
May inhibit androgen feedback on pituitary gland.
| Drug Name | Finasteride (Proscar, Propecia) |
|---|---|
| Description | Blocks conversion of testosterone to its more active metabolite, dihydrotestosterone. More effective when used in combination with OCPs. |
| Adult Dose | 1 mg PO qd |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; lactation; childhood |
| Interactions | None reported |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Minimum of 6 mo treatment necessary to determine response; caution in liver function abnormalities; monitor patients with severely diminished urinary flow for obstructive uropathy (may not be candidates for this therapy) |
| Drug Name | Spironolactone (Aldactone) |
|---|---|
| Description | Aldosterone antagonist that inhibits ovarian and adrenal production of androgens. Competes with dihydrotestosterone binding at hormone receptor sites on hair follicle cells. Also reduces 17alpha-hydroxylase activity, lowering plasma levels of testosterone and androstenedione. |
| Adult Dose | 200 mg/d PO qd or divided bid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; anuria; renal failure; hyperkalemia |
| Interactions | May decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Caution in renal and hepatic impairment; electrolytes and blood pressure should be monitored for first few weeks of therapy to be certain hypotension and hyperkalemia do not occur |
Drug Category: Glucocorticoids
May be used to correct adrenal insufficiency.
| Drug Name | Fludrocortisone (Florinef) |
|---|---|
| Description | Partial replacement therapy for primary and secondary adrenocortical insufficiency. |
| Adult Dose | 0.1 mg PO qd |
| Pediatric Dose | 0.05-0.1 mg PO qd |
| Contraindications | Documented hypersensitivity; systemic fungal infections |
| Interactions | Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects; decreases salicylate levels |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Taper dose gradually when therapy is discontinued; caution in Addison disease, potassium loss, and sodium retention |
Drug Category: Antifungal agents
Inhibit a variety of cytochrome P-450 enzymes, including 11beta-hydroxylase and 17-alpha-hydroxylase, which in turn, inhibit steroid synthesis.
| Drug Name | Ketoconazole (Nizoral) |
|---|---|
| Description | Inhibits steroid synthesis at the level of 17-alpha-hydroxylase/17,20-lyase, a key enzyme in sex steroid production. Also inhibits testosterone binding to its binding globulin. In some cases, especially in children with markedly advanced bone age, a rapid decrease in sex hormone levels may trigger true central puberty. In this event, add GnRH analogs to the treatment regimen. |
| Adult Dose | 200-400 mg PO bid/tid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; fungal meningitis |
| Interactions | Isoniazid may decrease bioavailability; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels; decreases metabolism of repaglinide, thus increasing serum levels and effects |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (adverse effects avoided with dose of 200-400 mg/d); administer antacid, anticholinergics, or H2 blockers at least 2 h after taking ketoconazole |
Drug Category: Dopamine agonists
Directly stimulate postsynaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (believed to be dopamine).
Pergolide was withdrawn from the
| Drug Name | Pergolide (Permax) |
|---|---|
| Description | Pergolide withdrawn from US market. Inhibits secretion of prolactin (PRL); causes a transient rise in serum concentrations of GH and decreases serum concentrations of LH. |
| Adult Dose | Administered at initial dose of 25 g/d, and then at 50 g/d with gradual dose escalation, depending on extent of serum PRL normalization |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Antagonists such as the neuroleptics phenothiazine, butyrophenones, thioxanthenes, and metoclopramide may diminish effectiveness of pergolide, a dopamine agonist; because pergolide mesylate is more than 90% bound to plasma proteins, exercise caution if coadministered with other drugs known to affect protein binding |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | May cause valvular heart disease (yearly echocardiograms recommended for patients on chronic therapy); inhibits secretion of prolactin; causes transient rise in serum concentrations of growth hormone and decrease in serum concentrations of luteinizing hormone; adverse effects include nausea, hypotension, hallucinations, and somnolence; use caution in patients who have been treated for cardiac dysrhythmias; may cause or exacerbate preexisting states of confusion and hallucinations or dyskinesia |
Drug Category: Progestins
May be used for endometrial stabilization and organization of basal layer in chronic anovulation.
| Drug Name | Medroxyprogesterone acetate (Provera, Cycrin, Depo-Provera) |
|---|---|
| Description | Derivative of progesterone. Androgenic and anabolic effects have been noted, but apparently is devoid of significant estrogenic activity. Parenterally administered dosage form inhibits gonadotropin production, which in turn, prevents follicular maturation and ovulation. Available data indicate that this does not occur when the usually recommended PO dose is administered qd. When orally administered in the recommended doses to women adequately exposed to exogenous or endogenous estrogen, transforms the proliferative endometrium into a secretory one. |
| Adult Dose | 10 mg PO qd for first 10 d of menstrual cycle |
| Pediatric Dose | Not recommended |
| Contraindications | Documented hypersensitivity; cerebral apoplexy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction |
| Interactions | Aminoglutethimide may decrease effects by increasing hepatic metabolism of medroxyprogesterone |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Caution in asthma, depression, renal or cardiac dysfunction, or thromboembolic disorders |
Drug Category: Estrogens
May be used to build endometrial lining in acute and chronic anovulation.
| Drug Name | Estrogens, conjugated/equine (Premarin) |
|---|---|
| Description | May be used for restoration of regular menstrual cycles, which may prevent endometrial hyperplasia associated with anovulation. Improvements of hyperandrogenic effects occur in 60-100% of women but usually require a minimum of 6-12 mo of use. A pregnancy test should be performed before initiating therapy. If the woman has had no menstrual period for 3 mo, withdrawal bleeding should be induced by administration of 5-10 mg of medroxyprogesterone acetate (Provera) qd for 10 d; therapy is then begun with OCPs. |
| Adult Dose | 0.05 mg PO qd/tid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; thrombophlebitis; undiagnosed vaginal bleeding |
| Interactions | May reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; an increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use of ethinyl estradiol with hydantoins may cause spotting, breakthrough bleeding, and reduce contraceptive efficacy; increase in fluid retention caused by estrogen intake may reduce seizure control; antibiotics may alter GI flora and cause a reduction in absorption of PO contraceptives, which may reduce efficacy |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Exercise caution in patients diagnosed with hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease |
Drug Category: Nonsteroidal anti-inflammatory drugs
Reduce blood loss by 30-50% in cases of anovulatory bleeding.
| Drug Name | Ibuprofen (Advil, Motrin, Excedrin IB) |
|---|---|
| Description | Used for reduction in uterine bleeding and dysmenorrhea associated with anovulatory cycles. Blocks formation of prostacyclin, an antagonist of thromboxane, a substance that accelerates platelet aggregation and initiates coagulation. Because NSAIDs inhibit blood prostacyclin formation, they might effectively decrease uterine blood flow. |
| Adult Dose | 200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d |
| Pediatric Dose | <12>12 years: Administer as in adults |
| Contraindications | Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding |
| Interactions | Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy |
