Interaction between oral contraceptives and other drugs

Pharraac.Ther.Vol.7, pp. 617-626.

0163-7258/79/1101-0617/$5.00/D

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INTERACTIONS CONTRACEPTIVES

BETWEEN ORAL AND OTHER DRUGS

ALASDAIR M . BRECKENRIDGE, DAVID J. BACK a n d MICHAEL ORME

Department of Pharmacology and Therapeutics, University of liverpool, P.O. Box 147, Liverpool, L69 3BX, UK

In modern therapeutics it is not uncommon for a patient to be receiving more than one form of drug treatment. It is estimated that 50 million women are currently prescribed oral contraceptive steroids (Pietrow and Lee, 1974) and many of these at some stage will receive other medication. Because of the low failure rate of contraceptive steroids when taken as prescribed, it has been customary to ascribe contraceptive failure to patient non-compliance. However, there is increasing evidence that certain commonly prescribed drugs can interact with oral contraceptive steroids leading to an impairment of contraceptive efficacy (Robertson and Johnson, 1976; Stockley, 1976). In addition, there is the problem of contraceptive steroids influencing the response to other drug therapy.

1. EFFECT OF OTHER DRUGS ON CONTRACEPTIVE STEROIDS The first clinical report of a drug-contraceptive steroid interaction appeared in 1971 when Reimers and Jezek observed an increased incidence of intermenstrual bleeding in users of contraceptive steroids who were also receiving antituberculous therapy. Since then further reports have confirmed the findings of Reimers and Jezek and in addition have implicated anticonvulsant drugs, antibiotics and certain CNS-active drugs in contraceptive failure. Although in terms of world usage of contraceptive steroids the number of reports of failure due to a drug interaction is small, it is worth bearing in mind that the recent introduction of low dose oestrogen preparations containing only 20 or 30/tg may mean that these interactions will assume greater importance. Two points need to be stressed however; (i) there is tremendous inter-individual variation in drug-drug interactions and (ii) it is difficult to extrapolate from one type of contraceptive preparation to another, bearing in mind the different synthetic steroids and dosages used. 1.1. ANTITUBERCULOUSDRUGS In 1971, Reimers and Jezek reported a study of 51 women who received antituberculous drugs concurrently with contraceptive steroid therapy. In 38 women who received rifampicin as part of their antituberculous therapy there was an increased incidence of intermenstrual bleeding compared to 13 women who were treated with antituberculous drugs which did not include rifampicin. Since this report at least 17 pregnancies have been reported (Table 1) in users of contraceptive steroids who were also receiving anti-tuberculous therapy. In each case rifampicin has been implicated as the interacting agent. In drug interaction studies in man, rifampicin has been shown to reduce the plasma half life of tolbutamide (Syvalahti et al., 1974; Zilly et al., 1975), hexobarbital (Zilly et al., 1975), warfarin (O'Reilly, 1974) and digitoxin (Zilly et al., 1977). The increased plasma clearance of drugs in patients treated with rifampicin has also been implicated in other studies. An increase in the daily dosage of oral anticoagulants was required in patients receiving concurrent rifampicin therapy (Michot et al., 1970; Bockhout-Mussert et al., 1974). Similarly in a patient with Addison's disease, increased corticosteroid dosage was necessary when the patient was receiving rifampicin (Edwards et al., 1974). 617

ALASDAIR M. BRECKENRIDGE,DAVID J. BACK and MICHAEL ORME

618

TABLE 1. Interaction of Antituberculous Drugs with OC Therapy--Clinical Data Report

Finding 5 pregnancies in 88 women on rifampicin and OC therapy. Pregnancy in woman on rifampicin, isoniazid & ethambutol and OC therapy. Pregnancy in woman on rifampicin, isoniazid & ethambutol and OC therapy. 3 pregnancies in 2 women on rifampicin, isoniazid & ethambutol and OC therapy. Pregnancy in woman on rifampicin and OC therapy. Pregnancy in woman on rifampicin, isoniazid & ethambutol and OC therapy. A woman became pregnant twice on rifampicin, isoniazid & ethambutol and OC therapy. 3 pregnancies in women on rifampicin, isoniazid & ethambutol (or Streptomycin) and OC therapy.

Nocke-Fink et al. (1973) Hirsch (1973) Kropp (1974) Hirsch et al. (1975) Piguet et al. (1975) Lafaix et al. (1976) Skolnick et al. (1976) Bessot et al. (1977)

In relation to contraceptive steroids, BoltBolt et al. (1977) demonstrated that rifampicin treatment (600mg for 6 days) resulted in the accelerated elimination of radioactive ethinyloestradiol from plasma. In 5 volunteers the elimination half life before rifampicin was 7.5 + 1.7 (S.D.) hours and after rifampicin was 3.3 +__0.9 hr. The increased plasma clearance of ethinyloestradiol is directly attributable to the enzyme inducing properties of rifampicin. Bolt et al. (1975) compared the hydroxylation rate of ethinyloestradiol in an in vitro system in liver biopsies from patients treated with rifampicin (600 mg for 6-10 days) and from patients not so treated. Treatment with rifampicin caused a four fold increase in the rate of hydroxylation at positions C-2/C-4 of ring A of the steroid and C-6/C-7 of ring B. In two patients cytochrome P-450 activity was significantly increased in the liver microsomal fraction. Enhanced metabolism of the oestrogenic component is clearly a major contributory factor of contraceptive failure in patients on rifampicin. Other studies (Back et al., 1977a) have shown that rifampicin also interacts with the progestogenic component. After a single dose of Minovlar® (1 mg norethisterone acetate + 50 #g ethinyloestradiol) to women both during and 5 weeks after rifampicin treatment there were marked changes in pharmacokinetic parameters (Table 2). Data for 6 patients are given. Peak plasma concentration, elimination (fl-phase) half life and the area under the curve (AUC) were significantly reduced during treatment. The results underline the marked interindividual variation seen in drug-drug interactions. TABLE 2. Pharmacokinetic Parameters of Norethisterone During (a ) and After (b ) rifampicin Treatment Name

Peak height ng/ml

A.U.C. h. ng. m l - 1

t½. fl (hr)

B.S.

a b

6.2 6.2

27.6 28.8

8.8 9.6

J.N.

a b

6.7 6.3

21.1 25.9

5.1 7.7

I.C.

a b

3.7 8.8

19.7 25.9

4.0 5.5

K.P.

a b

3.7 6.2

15.1 41.0

2.4 13.6

A.S.

a b

2.2 10.5

14.9 48.4

2.8 6.3

G.B.

a b

4.3 12.2

32.3 64.0

2.6 4.9

21.8 _ 7.0 39.0 + 15.3"

4.3 _+ 2.4 7.9 -4- 3.3*

Mean + S.D. a b

4.5 _+ 1.7 8.4 -4- 2.6*

* Significantly different from values during (a) rifampicin treatment at P < 0.05 (randomization test).

Oral contraceptive--drug interactions

619

TABLE 3. Interaction of Antiepileptiform Drugs with OC Therapy. Clinical Data

Report

Finding Pregnancy in woman on phenytoin, sulthiame, ferrous gluconate &folic acid and OC therapy Pregnancies in 4 women on anti-epileptiform drugs (phenobarbitone, primidone) and OC therapy. Pregnancy in woman on phenobarbitone and OC therapy

Kenyon (1972) Hempel et al. (1973)

3 pregnancies reported: 1. primidone + OC therapy 2. phenytoin, phenobarbitone and OC therapy 3. phenytoin, phenobarbitone, Ethosuccimide and OC therapy

Janz and Schmidt (1974)

It is therefore possible that part of the interaction of rifampicin with contraceptive steroids may be due to enhanced metabolic removal of the progestogenic component. At this stage it is difficult to assess the relative importance of removal of the oestrogenic and progestogenic component. 1.2. ANTICONVULSANT DRUGS

Breakthrough bleeding and failure on contraceptive therapy have been noted in patients taking anticonvulsant drugs and oral contraceptive steroids (Table 3). Phenobarbitone and to a lesser extent phenytoin and primidone are well documented microsomal enzyme inducers in man (reviewed by Breckenridge, 1975) and might therefore be expected to increase the rates of metabolism of the contraceptive steroids. In animals, barbiturates are powerful inducers of the enzymes responsible for the oxidative metabolism of many drugs (Conney, 1967) including steroids. Welch et al. (1968), showed that pretreatment of immature female rats with phenobarbitone (37 mg/kg twice daily for 4 days) caused accelerated' disappearance of tritiated oestradiol-17fl and oestrone from the body. Formation of polar metabolites was increased. Levin et al. (1968) studied the effect of pretreatment with phenobarbitone on the action of synthetic oestrogens and progestogens

10

b) rat

a) r a b b i t

,-,

Control

a-= pheno

o c D o O c

n=4

E --.....

.-,

n =4

Z

=-e p h e n o

Control

n=6 n= 4

g

\\,.

0

o 10C o 0

._~

I)

o o c

~ 1¢ n

1'2 tim. (.)

lh

14

;

time (.)

~

3

FIG. 1. Plasma concentration of norethisterone (ng/ml) in control and phenobarbitone treated rabbits (a) and rats (b). Animals were given norethisterone orally (rabbits--85#g/kg; rats--500 #g/kg).

620

ALASDAIR M. BRECKENRIDGE,DAVID J. BACK and MICHAEL ORME TABLE 4. Pharmacokinetic Parameters of Norethisterone in the Rabbit and Rat. Animals Were Given Norethisterone Orally (Rabbits--85 #g/kg; Rats--500/ag/kg) Control

Phenobarbitone

RABBIT Peak height (ng/ml) Elimination half life (hr) A.U.C. (h.ng.m1-1)

9.7 ___2.7 (4) 10.4 + 1.2 21.9 + 4.9

1.7t +_ 0.2 (4) 10.7 + 0.5 4.6t + 0.4

RAT Peak height (ng/ml) Elimination half life (hr) A.U.C. (h.ng.m1-1)

20.5 ___4.7 (6) 1.8 + 0.2 20.9 + 2.5

8.5* + 3.9 (4) 1.4 + 0.3 9.0* + 1.5

Figure in parentheses denotes the number of animals in each group. A.U.C. is the area under the plasma concentration-time curve. * Significantly different from controls, P < 0.05. t Significantly different from controls, P < 0.01.

on the immature rat uterus. Various dosages of diethylstilboestrol, ethinyloestradiol, mestranol, norethynodrel and norethisterone were given orally 18 hr after the last dose of phenobarbitone (37 mg/kg twice daily for 4 days). The uterotrophic response to a 0.1-3.0 #g dose of synthetic oestrogen was markedly inhibited ; although much less inhibition occurred when the dose of oestrogen was increased to 12/~g. The uterotrophic response to norethynodrel and norethisterone was also inhibited. In an in vitro study Kappus et al. (1972) observed a three-fold increase in the rate of demethylation of mestranol to ethinyloestradiol in phenobarbitone pretreated rats. In a recent study (Back et al., 1977b), the effect of phenobarbitone on the plasma disappearance of nonrethisterone in rabbits and rats was assessed. Phenobarbitone was administered either in drinking water (1 mg/ml for 6 days) to rabbits, or intraperitoneally (40 mg/kg twice daily for 4 days) to rats. In the rabbit, phenobarbitone had no significant effect on plasma norethisterone concentration after i.v. administration but significantly reduced the plasma concentration after oral administration. Similarly in the rat, phenobarbitone had no significant effect on plasma norethisterone concentration after i.v. or hepatic portal venous administration but reduced plasma concentration after oral administration (Fig. 1). Since there was no significant change in the elimination phase half life (Table 4) it may be that phenobarbitone increases the already substantial first pass effect of norethisterone (Back et al., 1977b) and/or influences absorption from the gastrointestinal tract. A recent report (Backstrom and Sodergard, 1977) highlights a further possible contributory mechanism to the antiepileptiform--contraceptive steroid interaction. In seven epileptic women who were receiving phenytoin, and in some phenobarbitone or ethosuximide additionally, there was a significant increase in sex hormone binding globulin (SHBG) capacity compared to a control group. Since it is known that the progestogens dnorgestrel and norethisterone bind with high affinity to SHBG (Victor et al., 1976 ; Back et al., 1978a) it is suggested that an increase in SHBG, produced by the antiepileptiform drugs, may lead to a decrease in the 'free' circulation steroids. 1.3. ANTIBIOTICS

In 1973, Hempel et al., reported pregnancies in 2 women taking contraceptive steroids who had also been receiving chloramphenicol and sulphamethoxypyradizine. In 1975, Dossetor reported pregnancies in 3 patients who were also taking ampicillin. Other 'pill' users receiving ampicillin have suffered breakthrough bleeding (Robertson and Johnson, 1976). Additional information of a steroid-antibiotic interaction has been obtained by monitoring the urinary excretion of oestrogen in pregnant women. In a study by Pulkkinen and Willman (1971a) 25 women in their last month of pregnancy received ampicillin (2 g per day for 3 days). After 3 days of treatment urinary oestriol excretion averaged 57-64 per cent of the mean value for control days. Plasma oestriol concentrations averaged 52 per cent of the mean

Oral contraceptive--drug interactions

621

control values after 24 hr, 45 per cent after 48 hr and 51 per cent after 72 hr of ampicillin treatment. On termination of drug treatment control urinary and plasma oestriol concentrations were seen within two days. In other studies a decreased excretion of urinary oestriol was seen in women 37-40 weeks pregnant who received either phenoxymethylpenicillin (Pulkkinen and Willman, 1971b) or neomycin (Pulkkinen and Willman, 1973). Synthetic oestrogens and progestogens are extensively excreted in the bile, both in man and laboratory species (Fotherby, 1974; Smith, 1974), principally as glucuronide conjugates. Subsequently they undergo enterohepatic circulation (Smith, 1974; Steinetz et al., 1967; Hanasono and Fischer, 1974). Since the gut microflora are a major source of hydrolytic enzymes, notable fl-glucuronidase (Hawksworth et al., 1971 ; Kent et al., 1972) treatment with antibiotics may be expected to interfere with the hydrolysis of steroid conjugates and hence reduce or eliminate any steroid reabsorption from the gastrointestinal tract. In a recent study in rats (Back et al., 1978b) the biliary excretion of radioactive ethinyloestradiol and norethisterone was investigated both quantitatively and qualitatively. 71.1 per cent of a given dose of [3H] ethinyloestradiol ([3 H] EE2) and 76 per cent of a given dose of [3H] norethisterone ([3H] N) were excreted in the bile of female rats in 4 hr. The majority of radioactivity appeared in the glucuronide fraction. Characterization of the hydrolyzed glucuronide fraction obtained after administration of [3H] EE 2 gave evidence that approximately 10 per cent of the administered dose may be directly conjugated to form ethinyloestradiol glucuronide. In contrast, there was no evidence of direct conjugation of norethisterone. In order to study the effect of antibiotics on the enterohepatic circulation of EE2 and N a 'linked rat' preparation previously described by Ladomery, Ryan and Wright (1967) was used. In this preparation the bile duct cannula from a 'donor' rat is inserted into the duodenum of a 'recipient' rat. (Fig. 2). 15.4 per cent of a dose of [3H] EE2 administered to donor rats (i.v.) was excreted in the bile of control recipient rats in 7 hr. When recipient rats were pretreated with either neomycin or ampicillin (100 mg body wt-1 day-1 for 5 days, orally), 5.2 per cent and 6.0 per cent of the dose appeared in bile respectively (Fig. 3). With [-3H] N, 13.2 per cent of the dose was excreted in the bile of control recipient rats in 7 hr and this was reduced to 3.6 per cent in neomycin pretreated and 3.9 per cent in ampicillin pretreated animals (Fig. 4). Thus antibiotic treatment reduces the enterohepatic circulation of synthetic steroids in the rat. In man there is evidence that both norethisterone and ethinyloestrodiol can be directly conjugated with glucuronic acid (Braselton et al., 1977; Helton and Goldzieher, 1977). In the clinical context the important issue is whether or not enterohepatic circulation of the synthetic steroids contributes to the therapeutic blood level and hence contraceptive efficacy.

bile

collected

from

steroid

RECIPIENTRAT Controls

DONOR

& antibiotic

administered

RAT

treated

FIG. 2. T h e ' l i n k e d r a t ' p r e p a r a t i o n .

JPT Vol. 7, No. 3----N

to

622

ALASDAIR M . BRECKENRIDGE, DAVID J. BACK a n d MICHAEL ORME

l

16

14 .> -6 12 t~ o -o,

• --•

C o n t r o l s ( n= 3 )

~--:,

Neomycin treated ! n = 3 )

=--.

Ampicillin

treated

8

(n= 3)

i/

T/ •

! ! l

g

I

II~ " ~ ~ 1

I 2

I 3

I 4 Time

I . 5

I 6

I 7

(hours)

FIG. 3. Excretionof radioactivityin the bile of control (11 It) neomycintreated (~ ZX)and ampicillin treated (A A) recipientrats. 3H-ethinylestradiol(10 #Ci/kg; 10#g/kg) administered i.v. to donor rats. Each point is the mean +S.E.M. of 3 experiments.

1.4. ANALGESICS,TRANQUILLISERSAND OTHER CNS ACTIVE DRUGS Hempel et al. (1973) found a loss of contraceptive control in a number of women on contraceptive steroids and other drugs. Of 25 regular users of contraceptive steroids who became pregnant, 12 had taken phenacetin or pyrazolone containing analgesics, 5 had taken meprobamate or chlordiazepoxide and 1 had taken dihydroergotamine. In addition, there was an increased frequency of breakthrough bleeding when commercially available analgesics were administered. The authors suspected amidopyrine (a known microsomal enzyme inducer, Breckenridge, 1975) as the component most likely to be responsible for this interaction. 2. E F F E C T O F C O N T R A C E P T I V E STEROIDS O N O T H E R D R U G S 2.1. METABOLISM Alterations in the pharmacodynamics or pharmacokinetics of drugs in women taking oral contraceptive steroids remains less well documented. The evidence is equivocal. O'Malley et al. (1972) found a significant increase in antipyrine half-life in women taking oral contraceptive steroids compared to non-users, and suggested that drug-metabolising capacity was impaired. Carter et al. (1974) also found an increase in antipyrine half-life in 5 out of 8 subjects (as compared to their previous half-life) although as in the study of O'Malley et al. (1972) there was no change in phenylbutazone half-life. Caution must be exercized in interpreting and extrapolating the results of animal experiments. With low doses of oral contraceptive steroids (i.e. doses resembling that in oral contraceptive preparations) inhibition of drug metabolism is seen (O'Malley et al., 1972) whereas with higher doses the microsomal enzymes are induced (O'Malley et al., 1972 ; Briatico et al., 1976 ; Jori et al., 1969). 2.2. ANTICOAGULANTS It is now well established that women taking contraceptive steroids will show an increase in the plasma concentration of certain clotting factors, notably factor VII, as well as those

Oran contraceptive--drug interactions

623

16 14 12 0

10

o

8

g

._.

con,,.,

~--~

Neomycin Treated (n= 3)

*--*

Ampicillin Treated (n=3)

Tf.. l //

(°:,,

I!/"

l

/

V

6 I,M

4 2

. ~ ~2 1

,

,

,

,

3

4

5

6

J

7

Time (hours)

FIG. 4. Excretion of radioactivity in the bile of control (m El), neomycin treated (A A), and ampicillin treated (A A) recipient rats. 3H-norethisterone (10 #Ci/kg; 10/~g/kg) administered i.v. to donor rats. Each point is mean ___ S.E.M. of at least 3 experiments.

involved in clot destruction (Bingel and Benoit, 1973; Meade et al., 1976). Since oral anticoagulants act by inhibiting the synthesis of the vitamin K dependent clotting factors, prothrombin, factor VII, factor IX and factor X, it is not surprising that contraceptive steroids have been reported to reduce the effectiveness of oral anticoagulants (Schrogie et al., 1967). There is some evidence that norgestrel containing contraceptive steroids have less effect on the blood coagulation mechanism than other progestogens (Briggs, 1974). In this study the increase in factor VII caused by ethinylestradiol (0.05 mg) in combination with norethisterone (1 mg) was opposed by the same dose of ethinylestradiol in combination with dnorgestrel (0.25 rag). It is not clear, however, whether the interaction between contraceptive steroids and oral anticoagulants will be more marked with preparations containing norethisterone than with preparations containing norgestrel. 2.3. ANTIHYPERTENSIVE DRUGS Whilst there is no evidence that contraceptive steroids interact directly with antihypertensive drugs, there is nevertheless evidence of physiological antagonism. A number of reports have shown that oral contraceptives can initiate or exacerbate hypertension (Laragh et al., 1967; Clezy et al., 1972 ; Weir, 1976). Changes in blood pressure appear to be related to the oestrogen component causing an elevation of plasma renin substrate and a rise in plasma renin activity (Newton et al., 1968). If there is no resultant permanent damage to renal circulation, blood pressure levels return to normal within 3-6 months. Few patients develop severe hypertension on contraceptive steroids. 2.4. ANTIDIABET1C DRUGS

Spellacy (1969) showed that following carbohydrate ingestion in non-diabetic patients, blood glucose levels were increased after oral contraceptive therapy when compared to controls. In contrast, in diabetic patients receiving contraceptive steroids, most indications are of little or no alteration in the requirement of hypoglycaemic agents. The evidence of a

624

ALASDAIR M. BRECKENRIDGE,DAVID J. BACK and MICHAEL ORME

c l i n i c a l p r o b l e m is t h e r e f o r e s m a l l a n d m o s t d i a b e t i c p a t i e n t s c a n b e g i v e n o r a l c o n t r a c e p t i v e s t e r o i d s if n e c e s s a r y . 2.5. ANTIDEPRESSANTS

There are reports that patients given oestrogens are relatively resistant to the therapeutic effect of imipramine (Prange et al., 1972; Khurana, 1972). Such patients are more likely to develop the toxic side effects of extreme lethargy, nausea and headache. It has been suggested (Somani and Khurana, 1973) that oestrogens inhibit the metabolism of imipramine. This interaction although demonstrated with ethinyloestradiol (50 pg) has not been shown with a combined oral contraceptive preparation. 3. CONCLUSION Contraceptive steroids may interfere with the action of other drugs and more important, other drugs may cause the failure of contraceptive steroids. The interacting drugs discussed are not exhaustive but represent the areas of therapeutics where a clinical problem has been recognized. The occurrence of pregnancy in a women taking contraceptive steroids should not be automatically dismissed as 'pill failure'. In an age of polypharmacy, we need to be aware of the potential risk of giving certain drugs with oral contraceptive steroids.

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