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ALESSE (levonorgestrel, ethinyl estradiol) Drug Interactions

Drug Interactions

Overview

The concurrent administration of COCs with other substances may result in an altered response to either agent. Decreased ethinyl estradiol (EE) serum concentration may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the COC. During concomitant use of EE containing products and substances that may lead to decreased EE serum concentration, it is recommended that a nonhormonal back-up method of birth control (such as condoms and spermicide) be used in addition to the regular intake of ALESSE. In the case of prolonged use of such substances COCs should not be considered the primary contraceptive.

After discontinuation of substances that may lead to decreased EE serum concentrations, use of a nonhormonal back-up method is recommended for at least 7 days. Longer use of a back-up method is advisable after discontinuation of substances that have led to induction of hepatic microsomal enzymes, resulting in decreased EE serum concentrations. It may sometimes take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use and rate of elimination of the inducing substance.

Reduced effectiveness of the COC, should it occur, is more likely with the low-dose formulations. It is important to ascertain all drugs that a patient is taking, both prescription and non-prescription, before COCs are prescribed.

Examples of substances that may decrease serum EE concentrations:

  • Any substance that reduces gastrointestinal transit time
  • Hypericum perforatum, also known as St. John’s wort and ritonovir (possibly by induction of hepatic microsomal enzymes)
  • Substances that induce hepatic microsomal enzymes, such as rifampicin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, griseofulvin, topiramate, some protease inhibitors, modafinil

Examples of substances that may increase serum EE concentrations:

  • Atorvastatin
  • Competitive inhibitors for sulfation in the gastrointestinal wall, such as ascorbic acid (vitamin C) and acetaminophen (paracetamol).
  • Substances that inhibit cytochrome P 450 3A4 isoenzymes such as indinavir, fluconazole and troleandomycin.
  • Troleandomycin may increase the risk of intrahepatic cholestasis during coadministration with COCs.

EE may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes, or by inducing hepatic drug conjugation, particularly glucuronidation. Accordingly, plasma and tissue concentrations may either be increased (eg, cyclosporine, theophylline, corticosteroids) or decreased (eg, lamotrigine).

In patients treated with flunarizine, use of oral contraceptives has been reported to increase the risk of galactorrhea.

  • There have been reports of pregnancy when COCs were co-administered with certain antibiotics (e.g., ampicillin and other penicillins, tetracyclines).

Concomitant use with the combination drug regimen ombitasvir, paritaprevir, ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS: Hepatic/Biliary/Pancreatic).  Therefore, COC users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with anti-viral HCV drug combinations such as ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin. COCs can be restarted 2 weeks following completion of treatment with an anti-viral HCV medicinal product.

The prescribing information of concomitant medications should be consulted to identify potential interactions.

For possible drug interactions with COCs, see DRUG INTERACTIONS: Drug-Drug Interactions: Tables 3 and 4.

Drug-Drug Interactions

Table 3*: Drugs That May Decrease the Efficacy of Oral Contraceptives
Class of
Compound
DrugProposed MechanismSuggested Management
AntibioticsAmpicillin
Penicillin
Intestinal hurry.For short course, use additional method or use another drug. For long course, use another method.
CotrimoxazoleEnterohepatic circulation disturbance, intestinal hurry.

For short course, use additional method or use another drug.


For long course, use another method.

Rifabutin
Rifampin
Increased metabolism of progestins. Suspected acceleration of estrogen metabolism.Use another method.
Chloramphenicol
Metronidazole
Neomycin
Nitrofurantoin
Sulfonamide
Tetracyclines
Induction of hepatic microsomal enzymes. Also disturbance of enterohepatic circulation, except for tetracyclines.For short course, use additional method or use another drug.

For long course, use another method.
TroleandomycinMay retard metabolism of OCs, increasing the risk of cholestatic jaundice. 
AnticonvulsantsCarbamazepine
Ethosuximide
Felbamate
Lamotrigine
Oxcarbazine
Phenobarbital
Phenytoin
Primidone
Topiramate
Induction of hepatic microsomal enzymes. Rapid metabolism of estrogen and increased binding of progestin and ethinyl estradiol to SHBG.Use higher dose OCs (50 mcg ethinyl estradiol), another drug or another method.
AntifungalsGriseofulvinStimulation of hepatic metabolism of contraceptive sterioids may occur.Use another method.
Cholesterol
Lowering
Agents
ClofibrateReduces elevated serum triglycerides and cholesterol.; this reduces OC efficacyUse another method.
HIV Protease
Inhibitors
RitonavirInduction of hepatic microsomal enzymes.Use another drug or another method.
Non-nucleoside
reverse
transcriptase
inhibitors
NevirapineInduction of hepatic microsomal enzymes
 
Use another drug or another method.
Sedatives and
Hypnotics
 
Benzodiazepines
Barbiturates
Chloral Hydrate
Glutethimide
Meprobamate
Induction of hepatic microsomal enzymes.For short course, use additional method or another drug.

For long course, use another method or higher dose OCs.
Antacids Decreased intestinal absorption of progestins.Dose two hours apart
Other DrugsPhenylbutazone**
Antihistamines**
Analgesics**
Antimigraine Preparations**
Vitamin E
Reduced OC efficacy has been reported.
Remains to be confirmed.
 

*Adapted from Dickey, RP, ed.: Managing Contraceptive Pill Patients, 5th edition Creative Informatics Inc., Durant, OK, 1987

** Refer to Oral Contraceptives 1994, A Report by the Special Advisory Committee on Reproductive Physiology to the Drugs Directorate, Health Protection Branch, Health Canada

Table 4*: Modification of Other Drug Action by Oral Contraceptives
Class of
Compound
DrugProposed MechanismSuggested Management

Alcohol
 Possible increased levels of ethanol or acetaldehyde.Use with caution.
Alpha-II
Adrenoreceptor
Agents
 
ClonidineSedation effect increased.Use with caution.
AnticoagulantsAllOCs increase clotting factors, decrease efficacy. However, OCs may potentiate action in some patients.Use another method.
AnticonvulsantsAllEstrogens may increase risk of seizures.Use another method.
LamotrigeneDecrease lamotrigine levels, may lead to breakthrough seizures.Use another method.
Antidiabetic
Drugs
Oral Hypoglycemics and
Insulin
OCs may impair glucose tolerance. and increase blood glucose.Use low-dose estrogen and
progestin OC or another method.
Monitor blood glucose.
Antihypertensive
Agents
Guanethidine and
Methyldopa
Estrogen component causes sodium retention, progestin has no effect.Use low-dose estrogen OC or use another method.
Beta BlockersIncreased drug effect (decreased metabolism)Adjust dose of drug if necessary.
Monitor cardiovascular status.
AntipyreticsAcetaminophenIncreased metabolism and renal clearance.Dose of drug may have to be increased.
 AntipyrineImpaired metabolism.Decrease dose of drug.
 ASAEffects of ASA may be decreased by the short-term use of OCs.Patients on chronic ASA therapy may require an increase in ASA dosage.

Anti-viral
hepatitis C virus

Ombitasvir
Paritaprevir
Ritonavir
Dasabuvir
May increase the risk of ALT elevations

Concomitant use is contraindicated (see CONTAINDICATIONS).

Aminocaproic
Acid
 Theoretically, a hypercoagulable state may occur because OCs augment clotting factors.Avoid concomitant use.
Betamimetic
Agents
IsoproterenolEstrogen causes decreased response to these drugs.Adjust dose of drug as necessary. Discontinuing OCs can result in excessive drug activity.
Caffeine The actions of caffeine may be enhanced as OCs may impair the hepatic metabolism of caffeineUse with caution.
Cholesterol-
lowering Agents
ClofibrateTheir action may be antagonized by OCs. OCs may also increase metabolism of clofibrate.May need to increase dose of clofibrate.
CorticosteroidsPrednisoneMarkedly increases serum levels.Possible need for decrease in dose.
Cyclosporine May lead to an increase in cyclosporine levels and hepatoxicity.Monitor hepatic function. The cyclosporine dose may have to be decreased.
Folic Acid OCs have been reported to impair folate metabolism.May need to increase dietary intake, or supplement.
Meperidine Possible increased analgesia and CNS depression due to decreased metabolism of meperidine.Use combination with caution.
Phenothiazine
Tranquilizers
All phenothiazines,
Reserpine, and similar
drugs.
Estrogen potentiates the hyperprolactinemia effect of these drugs.Use other drugs or lower dose OCs. If galactorrhea or hyperprolactinemia occurs, use other method.
Sedatives and
Hypnotics
Chlordiazepoxide
Lorazepam
Oxazepam
Diazepam
Increased effect (increased metabolism)Use with caution.
TheophyllineAllDecreased oxidation, leading to possible toxicity.Use with caution. Monitor theophylline levels.
Tricyclic
Antidepressants
Clomipramine
(possibly others)
Increased side effects: i.e., depression.
Increased serum levels due to decreased clearance.
 
Use with caution.
Vitamin B12 

OCs have been reported to reduce serum levels of Vitamin B12.
 

May need to increase dietary intake, or supplement.

*Adapted from Dickey, RP, ed.: Managing Contraceptive Pill Patients, 5th edition Creative Informatics Inc., Durant, OK, 1987

Drug-Food Interactions

No data is available.

Drug-Herb Interactions

Hypericum perforatum, also known as St. John’s wort causes decrease in serum EE concentration possibly by induction of hepatic microsomal enzymes.

Drug-Laboratory Interactions

Results of laboratory tests should be interpreted in the light that the patient is on COCs. The following laboratory tests are modified:

Liver Function Tests 
Bromsulphthalein Retention Test (BSP)Moderate increase
AST (SGOT) and GGTMinor increase
Alkaline PhosphataseVariable increase
Serum BilirubinIncreased, particularly in conditions
predisposing to or associated with
hyperbilirubinemia
  
Coagulation Tests 
Factors II, VII, IX, X, XII and XIIIIncreased
Factor VIIIMild increase
Platelet aggregation and adhesivenessMild increase in response to common
aggregating agents
FibrinogenIncreased
PlasminogenMild increase
Antithrombin IIIMild decrease
Prothrombin TimeDecreased
  
Thyroid Function Tests 
Protein-bound Iodine (PBI)Increased
Total Serum Thyroxine (T3 andT4)Increased
Thyroid Stimulating Hormone (TSH)Unchanged
Free T3 Resin UptakeDecreased
  
Adrenocortical Function Tests 
Plasma CortisolIncreased
Cortisol Binding GlobulinIncreased
Dehydroepiandrosterone sulfate (DHEAS)Decreased
  
Miscellaneous Tests 
Serum FolateOccasionally decreased
Glucose Tolerance TestVariable decrease with return to normal after 6 to 12 months
Insulin ResponseMild to moderate decrease
c- Peptide ResponseMild to moderate decrease

Drug-Lifestyle Interactions

See WARNINGS AND PRECAUTIONS regarding cigarette smoking. The actions of caffeine may be enhanced as OCs may impair the hepatic metabolism of caffeine. Use with caution.
There may be possible increased levels of ethanol or acetaldehyde when combined with alcohol. Use with caution.

Non-Contraceptive Benefits Of Oral Contraceptives

Several health advantages other than contraception have been reported.

  1. Combination oral contraceptives reduce the incidence of cancer of the endometrium and ovaries.
  2. Oral contraceptives reduce the likelihood of developing benign breast disease and, as a result may decrease the incidence of breast biopsies.
  3. Oral contraceptives reduce the likelihood of development of functional ovarian cysts.
  4. Pill users have less menstrual blood loss and have more regular cycles thereby, reducing the chance of developing iron-deficiency anemia.
  5. The use of oral contraceptives may decrease the severity of dysmenorrhea and premenstrual syndrome, and may improve acne vulgaris, hirsutism, and other androgen- mediated disorders.
  6. Oral contraceptives decrease the incidence of acute pelvic inflammatory disease and reduce the incidence of ectopic pregnancy.
  7. Oral contraceptives have potential effects on endometriosis.

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