Megestrol Acetate (megestrol acetate)

No dosing information is available for this tab.

Megestrol acetate is administered orally.

Megestrol acetate oral suspensions containing 200 mg/5 mL are not bioequivalent with the more concentrated oral suspension containing 625 mg/5 mL (Megace(R) ES). Threfore, the formulations are not interchangeable on a mg-per-mg basis. Patients receiving Megace(R) ES should be informed about the formulation differences to avoid overdosing or underdosing of the drug.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Megestrol/Dofetilide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The active tubular secretion of dofetilide may be inhibited by megestrol.(1)

CLINICAL EFFECTS: The concurrent administration of dofetilide with megestrol may result in elevated levels and increased effects of dofetilide, including QT prolongation or torsades de pointes.(1)

PREDISPOSING FACTORS: Renal impairment may increase risk for excessive QTc prolongation as dofetilide is primarily renally eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, dofetilide must be dose adjusted for creatinine clearance < or = to 60 mL/min.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of dofetilide states that megestrol should not be used in patients on dofetilide. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting megestrol.(1)

DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Megestrol is believed to inhibit the cation transport system. Other agents that inhibit this system, including cimetidine, ketoconazole, trimethoprim, and verapamil, have been shown to increase dofetilide levels. Therefore, the manufacturer of dofetilide states that megestrol should not be used in patients on dofetilide.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Immunosuppressives; Immunomodulators/Filgotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic disease-modifying antirheumatic drugs (DMARDs), or other Janus kinase (JAK) inhibitors may result in additive or synergistic effects on the immune system.(1)

CLINICAL EFFECTS: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of filgotinib states that concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors is not recommended.(1)

DISCUSSION: Serious infections have been reported in patients receiving filgotinib. Caution should be used in patients with a higher incidence of serious infection, including elderly patients aged 75 years and older.(1)

Selected Immunosuppressants/Leflunomide; Teriflunomide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of leflunomide or teriflunomide and potent immunosuppressants may result in additive or synergistic effects on the immune system.(1,2) Leflunomide is a prodrug and is converted to its active metabolite teriflunomide.(1)

CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with immunosuppressants may result in an increased risk of serious infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If leflunomide or teriflunomide is used concurrently with immunosuppressive agents, chronic CBC monitoring should be performed more frequently, every month instead of every 6 to 8 weeks. If bone marrow suppression or a serious infection occurs, leflunomide or teriflunomide should be stopped and rapid drug elimination procedure should be performed.(1,2)

DISCUSSION: Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide or teriflunomide alone, but most frequently in patients taking concurrent immunosuppressants.(1,2) Severe and potentially fatal infections, including sepsis, have been reported in patients receiving leflunomide or teriflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Tuberculosis has also been reported.(1,2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Immunosuppressives; Immunomodulators/Covid-19 Vaccines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1-3)

CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Centers for Disease Control and Prevention (CDC),(1) Infectious Diseases Society of America (IDSA),(2) and the American College of Rheumatology (ACR)(3) have published guidances for COVID-19 vaccination in patients on immunosuppressants. The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(1) IDSA recommends timing COVID-19 vaccination at least 2 weeks before starting or at least 3 months after completing immunosuppressive therapy.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose.(3) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted, though the immune response will likely be blunted. COVID-19 vaccines should not be delayed in patients taking immunosuppressive therapies.(1-2) See below for specific recommendations for certain agents. B-cell depleting agents, including rituximab: The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy on a continuing basis should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered according to the current CDC recommendations for unvaccinated patients. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(1) IDSA recommends waiting for at least 3-6 months after the last infusion of B-cell depleting therapy before administering COVID-19 vaccines.(2) The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(3) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(1,2) The CDC includes abatacept, cyclophosphamide, and TNF-alpha and cytokine inhibitors in their general recommendation to hold therapy for at least 2 weeks following vaccination (1) while the ACR provides different recommendations:(3) *Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion. *Cyclophosphamide: When feasible, administer cyclophosphamide 1 week after each COVID-19 vaccine dose. *TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.

DISCUSSION: IDSA recommendations are based on cohort and case control studies in immunocompromised patients that found low to modest vaccine effectiveness (37-61%) but lower risks of COVID-19 association hospitalization, COVID-19 related mortality, and critical illness.(2) The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(3) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(3) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(3) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(3) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(3) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(3)

Medroxyprogesterone; Megestrol/Coumarin Anticoagulants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is unknown but may involve inhibition of anticoagulant metabolism by medroxyprogesterone and megestrol.(1,2)

CLINICAL EFFECTS: The concurrent use of medroxyprogesterone or megestrol and coumarin anticoagulants may increase international normalized ratio (INR) and result in an increased risk for bleeding.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with medroxyprogesterone or megestrol and a coumarin anticoagulant (e.g. warfarin) should have their INR closely monitored.(1) When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: A study of four patients on high-dose progestins (two patients on medroxyprogesterone 500 mg twice daily and two patients on megestrol 160 mg once daily) and warfarin found that the progestins decreased the clearance of warfarin by 34.8% (from 2.3 to 1.5 mL/h*kg BW) and increased the half-life of warfarin by 71.4% (from 43.4 to 74.4 hours).(2)

There is no enhanced messaging for this drug.

• Lactation
• Pregnancy

• Adrenocortical insufficiency

• Chronic heart failure
• Diabetes mellitus
• Hypertension
• Thromboembolic disorder

There is no enhanced messaging for this drug.

More Frequent

• Hypertension
• Skin rash

Less Frequent

• Anemia
• Bullous dermatitis

Rare or Very Rare

• Abnormal glucose tolerance
• Adrenocortical insufficiency
• Altered mental status
• Cardiomyopathy
• Chest pain
• Deep venous thrombosis
• Depression
• Diabetes mellitus
• Dyspnea
• Edema
• Hepatomegaly
• Hyperglycemia
• Leukopenia
• Peripheral edema
• Pulmonary thromboembolism
• Seizure disorder
• Thrombophlebitis
• Tumor flare reaction

More Frequent

• Diarrhea
• Erectile dysfunction
• Flatulence
• Insomnia
• Nausea
• Vomiting

Less Frequent

• Acute cognitive impairment
• Candidiasis
• Constipation
• Dyspepsia
• Fever
• General weakness
• Headache disorder
• Increased urinary frequency
• Infection
• Libido changes
• Sialorrhea
• Urinary tract infection
• Xerostomia

Rare or Very Rare

• Abnormal vaginal bleeding
• Acute abdominal pain
• Alopecia
• Cough
• Disturbance in thinking
• Gynecomastia
• Hyperhidrosis
• Hypoesthesia
• Pain
• Palpitations
• Paresthesia
• Peripheral sensory neuropathy
• Pharyngitis
• Pruritus of skin
• Toxic amblyopia
• Urinary incontinence

No enhanced messaging available.

No enhanced messaging available.

Although there are no adequate and controlled studies to date using megestrol acetate in pregnant women, the drug has been shown to produce fetal harm in rats. Administration of the drug to rats produced decreases in fetal weight and live births and feminization of male fetuses. No teratogenicity studies in animals have been performed using megestrol acetate dosages that are clinically relevant to humans. Although progestins have been used beginning in the first trimester of pregnancy to prevent habitual abortion, there is no adequate evidence from well-controlled studies to substantiate the efficacy of progestins for these uses during any phase of pregnancy; however, there is evidence of potential adverse effects on the fetus when these drugs are administered during pregnancy. In addition, in most women, the cause of abortion is a defective ovum, which progestins could not be expected to influence. Because of their uterine-relaxant effects, progestins may delay spontaneous abortion of fertilized defective ova. There is evidence of increased risk of hypospadias in male neonates associated with progestin use during pregnancy; however, there are insufficient data about the risk in female fetuses. Because of increased genital abnormalities caused by progestins in both male and female fetuses, the manufacturer states that megestrol acetate is not recommended during pregnancy. If a woman becomes pregnant while receiving megestrol acetate or is inadvertently exposed to the drug during pregnancy, she should notify her physician and should be advised of the potential risks to the fetus. Women of childbearing potential should be advised not to become pregnant while receiving megestrol acetate therapy, and they should be advised to use an effective form of contraception while receiving the drug.

The manufacturer states that because of the potential for serious adverse reactions to megestrol acetate in nursing infants, women receiving the drug should discontinue nursing.

No enhanced messaging available.