Instructions for Valprocom 300 Chrono prolonged-release tablets, film-coated, blister pack No. 100
Composition
active ingredients: sodium valproate/valproic acid;
1 tablet of Valprocom 300 Chrono contains 200 mg of sodium valproate and 87 mg of valproic acid (corresponding to 300 mg of sodium valproate per 1 tablet);
excipients: ethylcellulose, ammonium methacrylate copolymer (type B), colloidal anhydrous silicon dioxide, coating for coating (hypromellose, glycerin, ammonium methacrylate copolymer (type A), polyacrylate dispersion, polyethylene glycol 1500, talc).
Dosage form
Film-coated tablets, prolonged-release.
Main physicochemical properties: round tablets, with a biconvex surface, with a score on one side, covered with a white film coating.
Pharmacotherapeutic group
Antiepileptic drugs. Fatty acid derivatives.
ATX code N03A G01.
Pharmacological properties
Pharmacodynamics
Prolonged-acting anticonvulsant. Inhibits gamma-aminobutyric acid (GABA) transferase, inhibits GABA biotransformation (inactivation), stabilizes and increases its content in the central nervous system. Stimulates central GABAergic processes (including inhibitory stress-limiting), reduces excitability and convulsive readiness of the motor areas of the brain.
It exhibits tranquilizing properties, reduces feelings of fear, improves the mental state and mood of patients. Highly effective in absence seizures and temporal pseudo-absence seizures, ineffective in psychomotor seizures.
It is known that in pharmacological studies, valproate inhibited various experimentally induced seizures (generalized and focal). Similarly, in humans, the antiepileptic effect of valproate can also be observed in various types of epilepsy.
In some in vitro studies, valproate has been shown to promote HIV-1 replication. However, this effect is not very pronounced and is not reproducible in all experiments. The clinical implications of this observation in HIV-1 infected patients are unknown. These data should be taken into account when evaluating viral load measurements when sodium valproate is used in HIV-1 infected patients.
Pharmacokinetics
Absorption
The bioavailability of the drug is approximately 100%.
The drug Valprocom 300 Chrono is present in blood plasma in the form of valproic acid.
The drug Valprocom 300 Chrono is immediately absorbed in the gastrointestinal tract. Its absorption is constant and prolonged. Therefore, there are no peaks in the drug's plasma concentrations, and therapeutic concentrations of valproic acid are better maintained over time.
Distribution
The volume of distribution of valproic acid is mainly limited to the blood and extracellular fluid, which undergoes rapid metabolism.
Binding to blood proteins occurs mainly with albumin and is dose-dependent and saturable. At a total plasma concentration of valproic acid of 40-100 mg/l, the proportion of its free fraction is usually 6-15%.
The level of valproic acid in the cerebrospinal fluid is similar to the concentration of unbound substance in blood plasma (about 10%).
Valproic acid is removed by dialysis, but the volume of the removed fraction is significantly reduced due to its binding to albumin (about 10%).
The therapeutic efficacy of the drug is manifested at its concentration in the blood plasma from 40 to 100 mg/l (278-694 μmol/l). With regular use of the drug Valprocom 300 Chrono, the equilibrium concentration is established on the 3rd-4th day of therapy, in some cases - after a longer period of time. In the case of maintaining the total level of valproic acid in the blood plasma above 150 mg/l (1040 μmol/l), a reduction in the daily dose is necessary. More than 96% of the drug undergoes intensive metabolism in the liver, 90-95% binds to blood plasma proteins, mainly albumin. The drug penetrates the blood-brain barrier, through the placental barrier, when using the drug Valprocom 300 Chrono by breastfeeding women, valproic acid is excreted in breast milk (1-10% of the total concentration in blood serum).
Metabolism
The metabolism of Valproate 300 Chrono occurs mainly in the liver. The main metabolic pathways are conjugation with glucuronic acid and beta-oxidation. Unlike most other antiepileptic drugs, sodium valproate does not accelerate its own degradation or the degradation of other substances, such as estrogens-progestogens. This property indicates that it does not induce enzymes that are part of the cytochrome P 450 metabolic system.
Breeding
During long-term treatment, the mean plasma half-life of valproic acid in adults is 10.6 hours (but can range from 5 to 20 hours), which is the basis for a twice-daily dosing regimen.
In full-term infants, the half-life is 20-30 hours. However, it rapidly approaches adult values as the infant grows older. Valproic acid is excreted primarily by the kidneys.
A small fraction remains unchanged, but most is found in the urine as metabolites.
Pharmacokinetics in specific patient groups
The level of albumin binding is reduced. Therefore, the resulting increase in the free fraction of valproic acid in the blood plasma should be taken into account and the dose should be reduced accordingly.
In elderly patients
Changes in pharmacokinetic parameters were detected, but they were insignificant.
Thus, the patient's clinical response (seizure control) is crucial for dose selection.
Indication
The main indication for the use of Valproate 300 Chrono, preferably as monotherapy, is primary generalized epilepsy: petit mal seizures/absence epilepsy, massive bilateral myoclonic seizures, grand mal seizures with or without myoclonus, photosensitive forms of epilepsy.
Also as monotherapy or in combination with other antiepileptic drugs it is effective in the following diseases:
secondary generalized epilepsy, especially West syndrome (convulsions in young children) and Lennox-Gastaut syndrome; partial epilepsy with simple or complex symptoms (psychosensory forms, psychomotor forms); epilepsy with secondary generalization; mixed forms of epilepsy (generalized and partial).
Treatment of manic episodes associated with bipolar affective disorders in the presence of contraindications to the use of or intolerance to lithium.
Prevention of recurrence of dysthymic episodes in adult patients with bipolar disorder who have responded to valproate therapy for the treatment of manic episodes.
Contraindication
Pregnancy, except in cases where other treatments are ineffective (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding");
contraindicated for use in women of reproductive age unless the conditions of the "Pregnancy Prevention Program" are met (see sections "Special instructions for use" and "Use during pregnancy or breastfeeding");
Hypersensitivity to valproate, divalproate, valpromide or any of the components of the drug in history; acute hepatitis; chronic hepatitis; severe hepatitis in the patient's individual or family history, especially caused by drugs; hepatic porphyria;
combination with mefloquine and St. John's wort extract (see section "Interaction with other medicinal products and other types of interactions");
Valproate is contraindicated in patients with mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase gamma, such as Alpers-Huttenlocher syndrome, in children under two years of age suspected of having a polymerase gamma-related disorder, and in patients with a history of ornithine cycle disorders (see section "Special warnings and precautions for use");
urea cycle enzyme deficiency (see section "Special precautions for use").
Interaction with other medicinal products and other types of interactions
Contraindicated combinations
St. John's wort. Risk of decreased plasma concentrations and reduced efficacy of the anticonvulsant.
Not recommended combinations
Lamotrigine: Increased risk of serious skin reactions (toxic epidermal necrolysis). In addition, plasma concentrations of lamotrigine may be increased (reduction of its hepatic metabolism by sodium valproate).
If concomitant use of these drugs cannot be avoided, careful clinical monitoring of the patient's condition is required.
Penems: Risk of seizures due to rapid decrease in plasma valproic acid concentrations, which may reach levels below the detection threshold.
Combinations requiring special precautions for use.
Acetazolamide. Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.
Aztreonam. Risk of seizures due to decreased plasma valproic acid concentrations. Clinical monitoring of the patient, determination of plasma drug concentrations, and possible dose adjustment of the anticonvulsant during treatment with the antibacterial drug and after its withdrawal is necessary.
Carbamazepine. Increased plasma concentrations of the active metabolite of carbamazepine with signs of overdose. In addition, decreased plasma concentrations of valproic acid due to increased hepatic metabolism by carbamazepine. Clinical monitoring, determination of plasma drug concentrations, and dose adjustment of both anticonvulsants are indicated.
Felbamate: Increased serum valproic acid concentrations with risk of overdose. Clinical monitoring, laboratory monitoring and possible valproate dose adjustment are indicated during and after felbamate therapy.
Nimodipine (oral and parenteral). Risk of increasing plasma concentrations of nimodipine by 50%. Therefore, the dose of nimodipine should be reduced in patients with arterial hypertension.
Phenobarbital and primidone. Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.
Propofol: Possible increase in propofol blood levels. When used concomitantly with valproate, a reduction in the propofol dose should be considered.
Rifampicin: Risk of seizures due to increased hepatic metabolism of valproate. Clinical monitoring, laboratory monitoring, and possible dose adjustment of the anticonvulsant are indicated during and after rifampicin therapy.
Rufinamide: Increased rufinamide concentrations may occur, especially in children weighing less than 30 kg. For children weighing less than 30 kg, after titration, the total dose should not exceed 600 mg/day.
Topiramate: Increased risk of encephalopathy and hyperammonemia. Regular monitoring of clinical and laboratory parameters is indicated.
Zidovudine. Risk of increased adverse reactions to zidovudine, especially hematological, due to a decrease in its metabolism by valproic acid. Regular monitoring of clinical and laboratory parameters is indicated. During the first two months of combined treatment, a complete blood count should be performed to check for anemia.
Zonisamide: Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.
Other types of interaction
Oral contraceptives: Since valproate does not induce enzymes, it does not reduce the effectiveness of estrogen-progestogen hormonal contraception in women.
Lithium. Valproate 300 Chrono does not affect serum lithium levels.
Application features
Pregnancy prevention program
Due to the high teratogenic potential and the risk of developmental disorders in infants exposed to valproate in utero, Valprocom 300 Chrono should not be used in female children and adolescents, women of reproductive age and pregnant women, except in cases where other treatments are ineffective or intolerable. If treatment with other drugs is not possible, valproate is prescribed in accordance with the requirements of the "Pregnancy Prevention Program" (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Pregnancy Prevention Program Terms.
The doctor who prescribes the drug must:
in each case, assess the individual circumstances, involve the patient in discussing treatment options and ensure that the risks and measures to minimise the risks are understood; assess the possibility of pregnancy in all patients; ensure that the patient understands and is aware of the risks of congenital malformations and neurodevelopmental disorders, in particular the significance of these risks for children exposed to valproate in utero; ensure that the patient understands the need for pregnancy testing before starting treatment and, if necessary, during treatment; advise the patient on methods of contraception and check the patient’s ability to continuously use effective methods of contraception throughout the course of valproate treatment (see also the section on Contraception below); ensure that the patient understands the need for regular (at least annual) review of treatment by a specialist experienced in the treatment of epilepsy; ensure that the patient understands the need to consult a doctor if she is planning a pregnancy, to discuss this issue in a timely manner and to switch to alternative treatment methods before conception and before the cessation of contraceptive methods; ensure that the patient understands the need to urgently consult her doctor in the event of pregnancy; issue an information booklet for the patient; ensure that the patient understands the dangers and the need for precautions associated with the use of valproate (annual risk information form).
These conditions also apply to women who are not currently sexually active, except in cases where, in the opinion of a doctor, there are compelling reasons to assert the absence of risk during pregnancy.
Female children
Pregnancy test. Pregnancy should be ruled out before starting valproate therapy. Valproate treatment should not be initiated in women of childbearing potential who have not had a negative pregnancy test using a plasma sample with a sensitivity of at least 25 mIU/ml, approved by a healthcare professional, to rule out unintended use during pregnancy. This pregnancy test should be repeated at regular intervals during treatment.
Contraception. Women of childbearing potential who are prescribed valproate should use effective contraception continuously throughout the duration of valproate treatment. These patients should be given comprehensive information on pregnancy prevention and referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user-independent form such as an intrauterine device or implant) or two complementary methods of contraception should be used, one of which should be a barrier method. The choice of contraceptive method should be based on an individual assessment of the patient's circumstances, with the patient's active participation and adherence to the doctor's recommendations. Even if the patient is amenorrhoeic, she should follow all recommendations for effective contraception.
Annual review of treatment by a specialist. The specialist should reassess at least annually whether valproate is the most appropriate treatment for the patient. The specialist should discuss the annual risk information form at the start of treatment and at each annual review of treatment and ensure that the patient understands the information provided. The annual risk information form should be duly completed and signed by the prescribing physician and the patient (or her legal representative).
Pregnancy planning. If a woman is planning to become pregnant, a specialist experienced in the management of epilepsy should re-evaluate valproate treatment and consider alternative treatments. Every effort should be made to switch the patient to acceptable alternative treatments before conception and before stopping contraception (see section "Use during pregnancy or breastfeeding"). If such a switch is not possible, the woman should receive further advice on the risks of valproate to the unborn child and make an informed decision about family planning.
Pregnancy: If a woman taking valproate becomes pregnant, she should be referred immediately to a specialist to re-evaluate valproate treatment and consider alternative treatments. Pregnant patients who have received valproate during pregnancy and their partners should be referred to a specialist with experience in teratology for evaluation and advice on treatment with the drug during pregnancy (see section “Use during pregnancy or lactation”).
The pharmacist should ensure that the patient is given the patient card each time valproate is dispensed and that the patient understands the information provided. In case of planned or suspected pregnancy, patients are advised not to stop taking valproate and to consult a specialist immediately.
Educational materials: To assist healthcare professionals and patients in avoiding the use of valproate during pregnancy, the marketing authorisation holder shall provide educational materials containing warnings on the teratogenicity (potential to cause birth defects) and fetotoxicity (potential to cause developmental disorders of the nervous system) of valproate, instructions on the use of valproate in women of childbearing potential and detailed information on the requirements of the Pregnancy Prevention Programme. A patient information leaflet and a patient card should be provided to all women of childbearing potential taking valproate.
An annual risk information form should be used and properly completed and signed at the time of initiation of treatment and at each annual review of valproate treatment by the specialist and the patient (or her legal representative).
Increased seizures. As with any antiepileptic drug, valproate may lead to a reversible increase in the frequency and severity of seizures (including status epilepticus) or the emergence of a new type of seizure, rather than an improvement in the condition. Patients should be advised to contact their doctor immediately if seizures worsen (see section 4.8).
These seizures must be differentiated from those that may be due to pharmacokinetic interactions (see section "Interaction with other medicinal products and other types of interactions"), toxicity (liver damage or encephalopathy, see sections "Special warnings and precautions for use" and "Adverse reactions") or overdose.
Since this drug is metabolized to valproic acid, it should not be combined with other drugs that undergo the same transformation to avoid valproic acid overdose (e.g. with semisodium valproate, valpromide).
Conditions. Cases of severe liver damage, sometimes fatal, have been reported. The highest risk, especially in combination with other antiepileptic drugs, is observed in infants and children under 3 years of age with severe epilepsy, particularly those with brain damage, mental retardation and/or genetically determined metabolic or degenerative diseases.
In children aged 3 and over, the risk is significantly reduced and continues to gradually decrease with age.
In most cases, such liver damage was observed within the first 6 months of treatment, usually within 2–12 weeks, and most often with complex antiepileptic therapy.
Signs to look out for. Early diagnosis is based on the clinical picture. In particular, the following symptoms should be considered, which may precede jaundice, especially in patients at risk (see above "Conditions of occurrence"):
nonspecific symptoms that appear suddenly, such as asthenia, anorexia, lethargy, drowsiness, sometimes associated with repeated episodes of vomiting and abdominal pain; in patients with epilepsy, recurrence of epileptic seizures despite proper adherence to therapy recommendations.
The patient (or their relatives if the patient is a child) should be informed of the need to seek immediate medical attention if such symptoms occur. The patient should be promptly evaluated, including clinical examination and laboratory tests of liver function.
Detection. Liver function tests should be performed before starting therapy and then regularly during the first 6 months of treatment. It should be emphasized that isolated and transient increases in transaminase levels without clinical signs are often observed, especially at the beginning of therapy. In addition to conventional studies, the most informative are studies that reflect protein synthesis, in particular prothrombin levels. In the event of confirmation of a pathologically low prothrombin level, especially in connection with other biological pathological indicators (significant decrease in fibrinogen and coagulation factors, increase in bilirubin and liver enzymes), therapy with Valproate 300 Chrono should be discontinued immediately. With simultaneous therapy with salicylates, their use should also be discontinued, since they have the same metabolic pathway. Laboratory tests should be repeated depending on the changes in the indicators detected.
Pancreatitis: Severe pancreatitis, sometimes fatal, has been reported very rarely. It can occur regardless of the age of the patient and the duration of treatment, but is particularly likely in young children.
Pancreatitis with an adverse clinical outcome is typically seen in young children or in patients with severe epilepsy, brain damage, and those receiving polytherapy with antiepileptic drugs.
If pancreatitis develops against the background of liver failure, the risk of fatal consequences increases significantly.
In case of acute abdominal pain or gastrointestinal symptoms such as nausea, vomiting and/or loss of appetite, the diagnosis of pancreatitis should be considered, and for patients with elevated pancreatic enzyme levels, the drug should be discontinued and alternative therapy should be used.
In children under 3 years of age, Valproate 300 Chrono should only be used as monotherapy. In patients of this age group, therapy should only be initiated after weighing the clinical benefits against the risk of liver damage or pancreatitis.
It is recommended to perform blood tests (complete blood count with platelet count, assessment of bleeding time and blood clotting parameters) before prescribing the drug, then after 15 days and upon completion of treatment, as well as before any surgical interventions and in case of hematomas or spontaneous bleeding (see section "Adverse reactions").
Renal impairment: In patients with renal impairment, a dose reduction may be necessary. Since plasma concentration data are sometimes difficult to interpret, the dose should be adjusted according to the clinical response.
Concomitant administration of salicylate derivatives to children should be avoided due to the risk of hepatotoxicity and bleeding.
This medicinal product is contraindicated in patients with urea cycle enzyme deficiency. Several cases of hyperammonemia with stupor or coma have been described in such patients (see section 4.3).
In children with a history of hepatic and gastrointestinal disorders of unknown origin (lack of appetite, vomiting, acute episodes of cytolysis), episodes of lethargy or coma, mental retardation, or a family history of neonatal or infant death, metabolic tests and especially fasting and postprandial ammonia tests should be performed before starting any valproate therapy.
At the beginning of treatment, the patient should be informed about the risk of weight gain, and appropriate measures should be taken to minimize this effect, which should mainly concern the diet.
Suicidal ideation and behavior: Suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs for multiple indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal ideation and behavior. The mechanism of this effect is unknown, and the currently available data do not allow us to exclude an increased risk with valproate.
Therefore, patients should be monitored for the early detection of suicidal thoughts and behavior and appropriate treatment should be administered. Patients (and caregivers of patients) should be warned that if signs of suicidal thoughts or behavior appear, they should seek medical advice immediately.
Effects of long-term treatment on bone metabolism. Cases of decreased bone mineral density, which may indicate osteopenia or osteoporosis and even lead to atypical fractures, have been reported in patients receiving long-term treatment with valproic acid. The mechanism of action of valproic acid on bone metabolism is not yet clear (see section "Adverse reactions").
Carbapenems. Concomitant use of Valproate 300 Chrono and carbapenems is not recommended (see section “Interaction with other medicinal products and other types of interactions”).
Patients with known or suspected mitochondrial disease: Valproate may provoke or exacerbate the clinical symptoms of existing mitochondrial diseases caused by mutations in mitochondrial DNA as well as the nuclear gene encoding the mitochondrial enzyme polymerase gamma (POLG).
In particular, valproate-induced acute liver failure and deaths due to hepatic dysfunction have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the POLG gene (e.g. Alpers-Huttenlocher syndrome). POLG-related disorders should be suspected in patients with a family history of POLG-related disorders or who present with symptoms suggestive of such a disorder, including (but not limited to) encephalopathy of unknown origin, refractory epilepsy (focal, myoclonic), status epilepticus, developmental delay, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. Testing for POLG mutations should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders (see Contraindications).
Interaction with other medicinal products: This medicinal product is not recommended for concomitant administration with lamotrigine and penems (see section “Interaction with other medicinal products and other forms of interaction”).
1 tablet of this medicinal product contains 47 mg of sodium. This should be taken into account by patients on a strict low-sodium diet.
Cognitive or extrapyramidal disorders. Cognitive or extrapyramidal disorders may be accompanied by signs of brain atrophy on imaging studies. Therefore, this type of clinical picture may be mistaken for dementia or Parkinson's disease. These disorders are reversible after discontinuation of the drug (see section "Adverse reactions").
Patients with concomitant carnitine palmitoyltransferase (CPT) type II deficiency should be warned about the increased risk of rhabdomyolysis when taking valproate.
Alcohol: You should not drink alcoholic beverages during treatment with valproate.
Effects on laboratory and diagnostic tests: Since valproate is excreted mainly by the kidneys, partly in the form of ketone bodies, urine tests for ketone bodies may give false positive results in patients with diabetes.
Ability to influence reaction speed when driving vehicles or other mechanisms
Valproate 300 Chrono affects the ability to drive or use machines due to the possible development of adverse reactions. Patients should be warned about the risk of drowsiness, especially in the case of anticonvulsant polytherapy or when using the drug in combination with benzodiazepines (see section "Interaction with other medicinal products and other types of interactions").
Use during pregnancy or breastfeeding
Valproate is contraindicated (see sections "Contraindications" and "Special Instructions for Use"):
during pregnancy, except in cases where other treatment methods are ineffective; to women of reproductive age, unless the conditions of the "Pregnancy Prevention Program" are met.
A meta-analysis including registries and cohort studies reported that 10.73% of children born to women with epilepsy who received valproate monotherapy during pregnancy had congenital malformations (95% confidence interval (CI): 8.16-13.29). This risk of the most common malformations is higher than in the general population, where the risk is approximately 2-3%. This risk is dose-dependent, but no threshold dose below which there is no risk can be established. The available data suggest an increased incidence of rare and common malformations.
The most common defects are those associated with impaired closure of the embryonic neural tube (approximately 2–3%), facial dysmorphism, cleft lip and palate, craniostenosis, malformations of the heart, kidneys, and genitourinary system (especially hypospadias), limb defects (including bilateral radial aplasia), and multiple anomalies of various body systems.
Developmental disorders
It is known that intrauterine exposure to valproate may cause adverse effects on the mental and physical development of children. This risk is likely to be dose-dependent, but the available data do not allow for a threshold dose below which the risk is absent. The exact period of pregnancy during which the risk of these effects exists has not been determined, and the possibility of a risk throughout the entire pregnancy cannot be excluded. Studies of preschool children exposed to valproate in utero have been reported to show that approximately 30-40% of children experience developmental delays, such as delayed speech and gait, reduced intellectual function, poor language skills (spoken and understood) and memory impairment.
There is evidence that the intelligence quotient (IQ) measured in school-age children (age 6) exposed to valproate during fetal development was on average 7-10 points lower than in children exposed to other antiepileptic drugs.
Although the role of other factors cannot be excluded, there is evidence that the risk of intellectual impairment in children exposed to valproate may be independent of maternal IQ. Data on long-term outcomes are limited.
Available evidence suggests that children exposed to valproate in utero have an increased risk of autism spectrum disorders (approximately 3-fold) and childhood autism (approximately 5-fold) compared with the general population studied.
Some evidence suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit hyperactivity disorder.
Women of reproductive age. Valproate 300 Chrono should not be used in women of reproductive age, except when other treatments are ineffective or poorly tolerated by the patient. If other treatments are not possible, Valproate 300 Chrono should only be prescribed if the requirements of the Pregnancy Prevention Program (see section "Special instructions") are met, including:
the patient is not pregnant (negative results of a pregnancy test using blood plasma with a sensitivity of at least 25 mIU/ml at the beginning of treatment and periodically during treatment); the patient uses at least one effective method of contraception; the patient is informed about the risks of valproate use during pregnancy.
In women of reproductive age, the benefit/risk ratio should be reassessed at regular intervals during treatment (at least annually).
If a woman is planning a pregnancy. Valproate treatment in women planning to become pregnant or who are pregnant should be re-evaluated. If possible, every effort should be made to substitute the drug for women planning to become pregnant with an appropriate alternative.
